Newness of drugs and use of HMO services by asthma patients.

OBJECTIVE: To define newness of drug technology and show associations between two measures of newness and health service utilization. METHODS: Healthcare use and changes in severity at each office visit were assessed for 1309 asthma patients from six health maintenance organizations (HMOs) during 1992. The age of each drug product, derived by subtracting its Food and Drug Administration (FDA) approval date from January 1, 1992, was used to construct two newness measures: the average age of all asthma drugs and, separately, all non-asthma drugs a patient used during the year and the percentages of a patient's asthma drugs from each of four time intervals of asthma drug breakthroughs. Service utilization variables included all primary care provider (PCP) visits, total prescription costs, emergency department (ED) visits, and hospitalizations. RESULTS: Using either measure of drug newness, multivariate analyses showed an association between greater use of newer asthma drugs and lower overall drug costs and fewer PCP visits. A trend was found between greater use of newer asthma drugs and fewer hospitalizations and ED visits. Newer non-asthma medications were associated with fewer ED visits. CONCLUSIONS: After controlling for patient and site variables, greater use of newer asthma drugs was associated with significantly lower drug costs and fewer PCP visits; associations with hospitalization rates and ED visits, although lower, were not significant.

Practice models used by pharmacists in rural Minnesota to obtain Medicare reimbursement.

OBJECTIVES: (1) Define "incident-to" rules for Medicare reimbursement; (2) Describe how pharmacists can meet incident-to rules; (3) Provide examples of models of practice in rural areas that could be useful for meeting incident-to rules; and (4) Develop a strategy for creating a pharmacy practice model that could meet Medicare reimbursement rules in rural areas. DESIGN AND PARTICIPANTS: A survey of participants from the Pharmacy Rural Education, Practice and Policy Institute and the College of Pharmacy, University of Minnesota. SETTING: Community, hospital, and clinic practice sites in rural Minnesota. RESULTS: Four distinct models of practice have evolved that meet the incident-to rules of Medicare for reimbursement. Travel, proximity to physicians, and employment are the major determinants of the models described. CONCLUSION: Pharmacists in rural areas have demonstrated the ability to satisfy the incident-to rules for Medicare reimbursement. Collaborative agreements with physicians must include specific employment, practice, and supervisory relationships in order to satisfy these rules.

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.

Tetracaine, epinephrine (adrenalin), and cocaine (TAC) versus lidocaine, epinephrine, and tetracaine (LET) for anesthesia of lacerations in children.

STUDY OBJECTIVE: To compare the duration of anesthesia experienced with lidocaine, epinephrine, and tetracaine (LET) solution and that with tetracaine, epinephrine (Adrenalin), and cocaine (TAC) solution during suturing of uncomplicated lacerations on the face or scalp. DESIGN: Double-blind, randomized, controlled trial. SETTING: The emergency department of a university-affiliated private children's hospital. PARTICIPANTS: One hundred seventy-one children with lacerations on the face and scalp requiring suturing. INTERVENTIONS: After standard application of the anesthetic solution, patients were assessed for signs of discomfort before and during laceration repair. Duration of anesthesia during laceration repair was determined on the basis of the length of time after removal of the anesthetic solution to the first sign(s) of discomfort that required additional anesthesia. RESULTS: There was no statistical difference between TAC and LET in adequacy of anesthesia before suturing or in duration of anesthesia during suturing. CONCLUSION: LET is an effective alternative to TAC for topical anesthesia during suturing of uncomplicated lacerations on the face and scalp in children.

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.

Clinical efficacy of antimicrobial drugs for acute otitis media: metaanalysis of 5400 children from thirty-three randomized trials.

OBJECTIVE: To reconcile conflicting published reports concerning the absolute and comparative clinical efficacy of antimicrobial drugs for acute otitis media in children. STUDY SELECTION: Articles were identified by MEDLINE search, Current Contents, and references from review articles, textbook chapters, and retrieved reports. Randomized, controlled trials of therapeutic antimicrobial drugs used in the initial empiric therapy for simple acute otitis media were selected by independent, blinded observers, and scored on 11 measures of study validity. Thirty English and three foreign-language articles met all inclusion criteria. DATA EXTRACTION: Data were abstracted for an end point of complete clinical resolution (primary control), exclusive of middle ear effusion, within 7 to 14 days after therapy started. DATA SYNTHESIS: The spontaneous rate of primary control--without antibiotics or tympanocentesis--was 81% (95% confidence interval, 69% to 94%). Compared with placebo or no drug, antimicrobial therapy increased primary control by 13.7% (95% confidence interval, 8.2% to 19.2%). No significant differences were found in the comparative efficacy of various antimicrobial agents. Extending antimicrobial coverage to include beta-lactamase-producing organisms did not significantly increase the rates of primary control or resolution of middle ear effusion. Pretreatment tympanocentesis was positively associated with individual group primary control rates, negatively associated with the ability to detect differences in clinical efficacy and unassociated with resolution of MEE. CONCLUSIONS: Antimicrobial drugs have a modest but significant impact on the primary control of acute otitis media. Treatment with beta-lactamase-stable agents does not increase resolution of acute symptoms or middle ear effusion; initial therapy should be guided by considerations of safety, tolerability, and affordability, and not by the theoretical advantage of an extended antibacterial spectrum.

Prematurity prevention programs: an analysis of successes and failures.

OBJECTIVE: Our purpose was to assess the long-term results of established prematurity prevention programs. STUDY DESIGN: A population cohort of pregnant women from two major urban health care organizations were examined. Rates and cost-benefit analysis of prematurity and patient, system, or physician failures were analyzed. During 1990 1143 pregnant women were prospectively reviewed. RESULTS: A total of 11.8% of the mothers were high risk and responsible for 108 (50.2%) of the preterm deliveries. The preterm birth rate of all enrollees was 4.6%. One percent of the preterm neonates required level III care for complications. The average charge for a 35 week infant was 18 times, and a 36 week infant was five times more costly than a term infant. Patient, physician, and health care system failures occurred at different rates. CONCLUSIONS: This preterm prevention program resulted in low preterm birth rates. Potentially preventable preterm births most often occurred as a result of patient and physician failures.

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.

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.

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.

Substance use in rural Midwestern pregnant women.

OBJECTIVE: To determine the rate of prenatal use of cocaine, cannabis, amphetamines, opiates, and cigarettes in rural midwestern women by analysis of reported use of cigarettes, maternal urine drug screening at admission to labor and delivery, and newborn meconium screening. DESIGN: The cohort of all women presenting to labor and delivery and their newborns were screened by urine and meconium analysis. Demographic information was also collected and matched to the urine and meconium samples. SETTING: Four primary care hospitals in rural Minnesota. Hospitals range in size from 66 to 140 beds, with 400 to 780 deliveries each year. PARTICIPANTS: All women presenting to labor and delivery for evaluation of term or preterm labor between April 4, 1991, and October 4, 1991. MEASUREMENTS/MAIN RESULTS: Overall, drugs not administered during labor were found in a mean (+/- SD) of 3.2% +/- 1.1% of all urine screens. Cannabis was found in 1.2% +/- 0.7% of maternal urine samples, amphetamines in 0.8% +/- 0.58%, opiates in 1.2% +/- 0.7%, and cocaine in 0% +/- 0.3%. Meconium samples were positive in 1.8% +/- 0.9% of cases. Cannabis was found in 1.1% +/- 0.7% of meconium samples, opiates in 0.6% +/- 0.5%, and cocaine in 0.1% +/- 0.1%. No urine samples were positive for more than one drug. One meconium sample tested positive for both cocaine and cannabis. Nearly 4% of patients had either a positive urine specimen or a positive meconium specimen. By history, 24.5% of women admitted to smoking during pregnancy. CONCLUSION: The use of cocaine, cannabis, opiates, and amphetamines was uncommon in this rural population. However, one quarter of the women admitted to smoking during pregnancy, exposing their fetuses to a dangerous substance.

The effect of heparin on three whole blood activated clotting tests and thrombin time.

Whole blood activated clotting time (ACT) can be determined by many different methods that use a variety of clotting cascade activators and end-points. This study compared the results of three whole blood ACT instruments at equivalent concentrations of heparin. Whole blood (9.8 ml) from 10 healthy adult volunteers without coagulation abnormalities was added to 0.2 ml of heparin solution producing heparin concentrations of 0, 0.1, 0.2, 0.4, 0.6, 0.8, and 1.0 U/ml. Coagulation status was determined in duplicate with the Hemochron 400 System (HC), the HemoTec Automated Coagulation Timer (HT), and the TriMed ACTivator (TM). Thrombin times or dilutions (TT) were also determined for each sample. Baseline values did not differ (p greater than 0.05); however, the HT and TM ACT values were significantly longer (p less than 0.05) than the HC ACT values at predicted heparin concentrations greater than 0.2 U/ml. Results from the HT and TM instruments were not significantly different. The HT and TM instruments both provided a greater ACT range over the heparin concentrations tested. Of the tests studied to monitor heparin therapy, mean scaled TTs showed the best correlation with predicted heparin concentrations.

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.

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.

Procedural variables which affect activated clotting time test results during extracorporeal membrane oxygenation therapy.

Hemorrhage secondary to heparin therapy is one of the most serious risks of extracorporeal membrane oxygenation (ECMO). This study determined those variables which affect the precision of activated clotting time (ACT) measurements used to monitor heparin therapy. Heparin therapy of eight neonatal lambs was monitored during ECMO with two Hemochron 400 machines to determine the effects of intermachine variability, test volume, speed and direction of agitation, and interpersonnel variability on ACT values. Test volume (0.25 vs. 0.4 ml) and agitation speed (2 shakes/sec vs. one shake/sec) resulted in significantly different ACT values (p less than .05). The mean matched ACT values determined from different agitation directions (vertical vs. horizontal) or the use of a stepper pipette to measure test volume vs. visual estimation of test volume were not significantly different. Variability in ACT test results is significantly increased by variations in test volume or agitation (speed and direction), intermachine variability, and by interpersonnel technique. These variables should be considered when devising protocols for ACT monitoring and management of heparin therapy.

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.

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.

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)

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.