Antenatal magnesium sulfate and spontaneous intestinal perforation in infants less than 25 weeks gestation.

OBJECTIVE: Evaluate spontaneous intestinal perforation (SIP)/death among extremely low birthweight (ELBW) infants before, during and after initiation of an antenatal magnesium for neuroprotection protocol (MgPro). STUDY DESIGN: We tested associations between SIP/death and magnesium exposure, gestational age (GA) and interactions with GA and magnesium exposure in a cohort of inborn ELBW infants before, during and after MgPro. RESULT: One hundred and fifty-five ELBW infants were included, 81 before, 23 during and 51 after MgPro. ELBW infants (78.3%) were exposed to Mg during MgPro compared with 50.6% and 60.8% before and after, respectively. Incidence of SIP on protocol was 30.4% vs 12.9% off protocol (P=0.03). GA was strongly associated with SIP (P<0.01). Antenatal Mg dose was also associated with SIP/death regardless of epoch (odds ratio 9.3 (1.04-104.6)), but increased SIP/death was limited to those <25 weeks gestation. CONCLUSION: Higher Mg dose was associated with higher SIP and death risk among infants with the lowest birthweights. Validation of this observation in larger populations is warranted.

Tissue-specificity of apoptosis in hepatoma-derived cell lines.

Apoptosis is known to play a critical role in development and homeostasis in metazoans. Although apoptotic responses vary widely among cell types, the underlying mechanisms responsible for these differences are not known. In order to understand the molecular basis for these differences, we have studied a cell culture model comparing hepatoma cells to dedifferentiated cell lines derived from them. We recently reported evidence suggesting that a common regulatory locus affects both liver-specific function and sensitivity to lipopolysaccharide (LPS)-mediated apoptosis. Here, we show that dedifferentiated hepatoma cells undergo apoptosis in response to multiple compounds, including sorbitol (to induce hyperosmotic shock), TNF alpha and the microtubule damaging agent vinblastin. In contrast, the hepatoma parental cells fail to undergo apoptosis in response to any of the compounds tested. Further analysis of LPS-mediated cell death found that antioxidants N-acetylcysteine and alpha-tocopherol partially prevented apoptosis. Lastly, evidence is presented showing that LPS-mediated cell death of the hepatoma variant cell lines is caspase-dependent. These results suggest that pathways dictating hepatic phenotype also affect general cellular survival mechanisms in response to multiple agents. The dedifferentiated cells provide a model to examine the influence of cell-type specific expression on apoptotic signaling.

Effectiveness and infant acceptance of the Rx medibottle versus the oral syringe.

STUDY OBJECTIVE: To compare the effectiveness and infant acceptance of drug delivery of the Rx medibottle with the standard oral syringe. DESIGN: Prospective open-label, randomized, crossover clinical study. SETTING: General pediatric outpatient clinic at an urban university. SUBJECTS: Thirty healthy, bottle-fed infants, aged 2-14 months, receiving routine vaccinations. INTERVENTION: Each infant received a single dose of acetaminophen (Tempra syrup), with one-half delivered by the Rx medibottle and one-half delivered with an oral syringe. MEASUREMENTS AND MAIN RESULTS: Three raters independently evaluated effectiveness and infant acceptance of each drug-delivery device. Effectiveness was based on the percentage of infants receiving 100% of the intended dose. Infant acceptance was scored using a validated infant medication acceptance scale (MAS, 10 = highest level). Significantly more infants received 100% of the intended dose with the Rx medibottle (93.3%) than with the oral syringe (56.7%, p=0.0074). Infants had a significantly higher mean MAS score when using the Rx medibottle (8.3+/-1.8 vs 7.3+/-1.7, p=0.002). In addition, a significantly higher percentage had ideal MAS scores of 9 or above with the Rx medibottle (73%) compared with the oral syringe (17%, p=0.0001). CONCLUSION: The Rx medibottle was more effective and had a higher level of infant acceptance than the oral syringe. Although further studies are necessary, this suggests that the Rx medibottle may be a better method of delivering liquid drug and may increase infant adherence.

Infant acceptance and effectiveness of a new oral liquid medication delivery system.

A medication acceptance scale (MAS) for pediatric oral liquids was developed and used to evaluate effectiveness and infant acceptance of a medication delivery system. The MAS incorporated five behavioral elements associated with pediatric drug administration: cry, facial expression, body movement or level of agitation, reaction to placement of medication in the mouth, and swallowing. A score of 1-10 was possible, with 10 indicating the highest level of infant acceptance. Preliminary field testing was conducted. In an open-label clinical study, a single dose of acetaminophen was administered to 20 infants with approximately one fluid ounce of infant formula or apple juice by pediatric nurses using the Rx medibottle (The Medicine Bottle Company). Past medication acceptance was rated on an infant global acceptance scale. The intended dose, the amount consumed, and the time taken to administer the dose were recorded. Infant acceptance was independently scored by a nurse and two pharmacists. A high preliminary estimate of internal consistency reliability of the MAS was found. Interrater reliability was high, with the highest correlation between the two pharmacists. Sixteen (80%) of the infants received 100% of the intended dose; it took 0.5-9 minutes to administer these doses. The median MAS score was 9 for each of the three raters. Mean MAS scores for the three raters were 7.85 and 7.45 (pharmacists) and 8.50 (nurse). There was a strong correlation between MAS scores and infant global acceptance scale scores. A pediatric oral liquid MAS that had content validity, concurrent validity, high internal consistency reliability, and high interrater reliability was developed; the Rx medibottle was an effective oral liquid medication delivery system and had a high level of infant and rater acceptance.

Defective NF-kappaB signaling in dedifferentiated hepatoma cells.

Dedifferentiated rat hepatoma cells contain defects that result in the loss of hepatic gene expression, including the liver-enriched HNF4/HNF1alpha pathway. We examined induction of NF-kappaB, a key mediator of the inflammatory response, in hepatoma and dedifferentiated hepatoma cells. We show that exposure of dedifferentiated hepatoma cells, but not rat and human hepatoma cell lines, to proinflammatory cytokines or lipopolysaccharide resulted in rapid and sustained NF-kappaB induction. IkappaB-beta levels, but not NF-kappaB subunit p65 or IkappaB-alpha levels, were elevated compared with those for parental hepatoma cells. Interestingly, LPS-mediated activation of NF-kappaB was found to be independent of degradation of IkappaB-alpha or IkappaB-beta. Thus, these results suggest that loci responsible for maintaining hepatic gene expression also influence cellular responses to inflammatory agents.

Pharmacokinetics and administration regimens of vancomycin in neonates, infants and children.

The increased use of vancomycin in neonatal and paediatric patients has prompted numerous pharmacokinetic studies and the development of many empirical administration methods. The majority of dosage guidelines use the relationship between pharmacokinetic parameters and patient variables such as chronological age, bodyweight, and/or measures of renal function. Currently, those dosage guidelines which are based upon postconceptional age and bodyweight seem to provide the best options for empirical administration in neonates and infants. In addition, serum creatinine may prove to be a useful guide to the empirical administration of vancomycin in neonates older than 7 to 14 days. Several investigators have reported the individualisation of dosage regimens based on pharmacokinetic-based administration methods. The most common techniques employed have been Sawchuk-Zaske method and Bayesian forecasting. However, only a limited number of studies have evaluated either empirical administration or individualised administration techniques in patient populations outside those of the original reports; this makes choosing between the methods difficult. Pharmacokinetic data and administration recommendations have gradually become available in special paediatric patient populations. The majority of studies have focused on patients requiring cardiopulmonary bypass surgery or with burns, cancer or central nervous system infections. However, a limited amount of information is available regarding vancomycin disposition in children older than 1 year of age with and without end-stage renal failure. The monitoring of serum vancomycin concentrations may be useful in selected neonatal and paediatric patient populations, especially where large interpatient variability occurs and administration guidelines are not clearly established. Similar to the literature on adults, the lack of conclusive evidence concerning the relationship between serum vancomycin concentrations and therapeutic responses leaves this topic open to debate.

Respiratory syncytial virus-immunoglobulin intravenous (RSV-IGIV) for respiratory syncytial viral infections: part I.

RSV is a highly contagious, devastating disease, especially in high-risk infants. RSV infection typically presents as an upper respiratory tract infection and then may progress to the lower respiratory tract, causing pneumonia and bronchiolitis. The signs, symptoms, and severity of RSV infection vary with age and the number of previous RSV infections. Young age, premature birth, a crowded living environment, day care attendance, and exposure to passive smoking are risk factors for more severe RSV disease. Treatment of RSV infection consists primarily of supportive care but may also include bronchodilators and ribavirin. RSV-IGIV provides passive immunity against RSV infections. RSV-IGIV has been shown to decrease the incidence of RSV hospitalization by 41% to 65% and the number of hospital days by 53% to 59%. The use of RSV-IGIV has also decreased the occurrence and duration of moderate/severe RSV infection. RSV-IGIV has an FDA-approved indication for the prevention of RSV-LRTI in infants less than 24 months of age who have BPD or were born prematurely (< or = 35 weeks' gestational age). RSV-IGIV is not approved for use in children with CHD.

Bayesian forecasting of serum vancomycin concentrations in neonates and infants.

A dynamic pharmacokinetic model for i.v. vancomycin administration was developed and tested in 47 neonates and infants. Twenty-nine patients (Group 1), having two or more concentrations, were used to estimate population parameters by nonlinear least-squares analysis. Multiple stepwise linear regression techniques showed that estimated creatinine clearance, Clcr, and postnatal age were significant demographic factors related to vancomycin clearance (CL). No strong associations were found for the apparent volume of distribution. A one-compartment model was constructed using the associations of CLcr and postnatal age with vancomycin CL. Eighteen patients (Group 2), receiving 35 courses of vancomycin therapy, with both initial and subsequent sets of peak and trough concentrations, were used to test the predictive performance of the model with and without the use of Bayesian forecasting. Using only population-based parameters, the respective mean error (ME) (bias) and mean absolute error (MAE) (precision) for predicting subsequent peak concentrations were -1.20 and 3.89 mg/L and for trough concentrations, 0.83 and 2.23 mg/L, respectively. For the Bayesian method, these values were, respectively, 0.45 and 4.13 mg/L for peak concentrations and 1.55 and 2.40 mg/L for trough concentrations. When predicted concentrations occurred within 30 days of feedback concentrations, the Bayesian method tended to be slightly less biased and more precise than the population-based parameters. The opposite was true > 30 days of the initial set of feedback concentrations. The use of population-specific pharmacokinetic parameters and Bayesian forecasting should allow accurate dosage regimen design as well as minimize the need for monitoring serum vancomycin concentrations in neonates and young infants.

Pharmacokinetics of intravaginal metronidazole gel.

The pharmacokinetics of a single 500 mg oral dose of metronidazole and 5 g of 0.75% metronidazole intravaginal gel (37.5 mg metronidazole) were compared in 12 adult volunteers in a randomized crossover manner. Serial serum samples were collected over a 48-hour period and analyzed for metronidazole and hydroxymetronidazole. Metronidazole serum concentrations after intravaginal administration were only 2% of concentrations seen with the standard 500-mg oral dose. The dose-adjusted maximum serum concentration (898 +/- 121 ng/mL vs. 237 +/- 69 ng/mL) and area under the serum concentration-time curve (9362 +/- 2873 ng * hr/mL vs. 4977 +/- 2671 ng * hr/mL) were significantly greater for the oral versus intravaginal dose of metronidazole. The time to reach maximum concentration (1.4 +/- 0.6 hr vs. 8.4 +/- 2.2 hr) was significantly shorter for the oral compared with the intravaginal dose. The mean bioavailability for the intravaginal gel was 56%. Our results show that the 0.75% gel formulation may offer the advantage of fewer systemic adverse effects compared with other formulations for the treatment of bacterial vaginosis.

Evaluation of universal hepatitis B immunization practices of Illinois pediatricians.

OBJECTIVE: To characterize universal hepatitis B immunization practices of pediatricians who routinely provide childhood immunizations in Illinois. DESIGN: Survey of 522 randomly chosen Illinois pediatricians. Student's t test, chi 2 analysis, and multivariate logistic regression were used to identify relationships between physician demographics and outcomes of interest. MAIN OUTCOME MEASURES: Physician agreement with the new Centers for Disease Control and Prevention Immunization Practices Advisory Committee and the American Academy of Pediatrics universal infant hepatitis B immunization guidelines, incorporation of the recommendations, routine hepatitis B immunization of older children (aged 6 months to 11 years), and routine hepatitis B immunization of adolescents. RESULTS: The survey response rate was 71.5%. Of those pediatricians routinely providing immunizations (N = 323), 72.8% agreed with and 90.1% have incorporated universal hepatitis B immunization; 36.5% and 53.0% routinely immunized older children and adolescents, respectively. Pediatricians practicing in medium-sized practices were half as likely to agree with the recommendations (odds ratio [OR], 0.51; 95% confidence interval [CI], 0.31 to 0.84). Cost and a belief that universal immunization of infants is not medically necessary were the two most commonly listed reasons for not incorporating the new guidelines. Percent reimbursement from public aid was negatively related to the routine immunization of older children (OR, 0.34; 95% CI, 0.12 to 0.95). Both percent reimbursement from self-pay (OR, 5.62; 95% CI, 2.25 to 14.05) and a rural location (OR, 0.16; 95% CI, 0.04 to 0.56) were related to routine hepatitis B immunization of adolescents. Gender and number of years in practice were not associated with physician response. CONCLUSIONS: The majority of Illinois pediatricians who routinely provide pediatric immunizations have incorporated the new universal hepatitis B immunization guidelines into their practices. Continued efforts to address financial barriers and to educate physicians may hasten the time when the transmission of the hepatitis B virus will no longer occur.

Pharmacokinetic evaluation of two theophylline dosing methods for infants.

Theophylline is often used in infants, yet few studies have evaluated the serum concentrations achieved with currently recommended dosing guidelines. Two theophylline dosing regimens, a postnatal age (PNA) equation and the Federal Drug Administration (FDA) dosing guidelines, were retrospectively evaluated in a group of infants, postconceptional age (PCA) 31-96 weeks, with known theophylline clearances. Large variations in theophylline concentrations were observed for both dosing regimens. Mean +/- SD projected steady-state theophylline serum concentrations, Css, were 17.7 +/- 7.6 micrograms/ml with the PNA equation (n = 40) and 5.6 +/- 2.9 micrograms/ml with the FDA guidelines (n = 52). Over one-third of Css with the PNA equation were > 20 micrograms/ml. Using the FDA guidelines, 40% of Css were < 5 micrograms/ml. The majority of infants < 40 weeks PCA attained projected Css > 20 micrograms/ml (21.7 +/- 5.1 micrograms/ml) with the PNA equation, but < 5 micrograms/ml (4.3 +/- 1.4 micrograms/ml) with FDA guidelines. An age-related bias was also observed for each dosing method. For the PNA equation, projected Css were significantly higher in infants < 40 weeks versus > or = 40 weeks PCA (21.7 +/- 5.1 versus 15.8 +/- 7.9 micrograms/ml, p < 0.01). For FDA guidelines, projected Css were significantly lower in infants < 40 weeks PCA versus older infants (4.3 +/- 1.4 versus 8.5 +/- 4.3 micrograms/ml, p < 0.001). Clinical application of currently accepted theophylline dosing guidelines for infants results in a high frequency of Css, which are potentially toxic or subtherapeutic.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in theophylline metabolism during the first year of life.

Maturational changes in theophylline disposition were evaluated in 52 infants (gestational age, 24 to 40 weeks; postnatal age, 2 to 69 weeks) receiving maintenance theophylline therapy. Theophylline and metabolites were measured in serum and urine at steady state, and the influence of clinical parameters on the maturational changes was analyzed by multiple stepwise linear regression. Theophylline clearance and urine metabolite pattern reached adult values at 55 weeks' postconceptional age. Serum caffeine concentrations greater than 1 microgram/ml occurred in infants up to 50 weeks' postconceptional age. Disappearance of serum caffeine concentrations and maturation of theophylline clearance were primarily related (p < 0.001) to development of the demethylation pathway to 3-methylxanthine. Postconceptional age was the major factor (p < 0.001) explaining the interpatient variability in theophylline clearance (r2 = 0.57), serum caffeine to theophylline ratio (r2 = 0.46), and urinary excretion of theophylline (r2 = 0.51), caffeine (r2 = 0.49), 1,3-methyluric acid (r2 = 0.32), 1-methyluric acid (r2 = 0.53), and 3-methylxanthine (r2 = 0.58). Our findings indicate that postconceptional age rather than postnatal age should be used as a maturational marker during theophylline therapy in infancy.

Bayesian forecasting of gentamicin pharmacokinetics in pediatric intensive care unit patients.

The predictive performance of a one compartment Bayesian forecasting program was evaluated in pediatric intensive care unit patients with normal renal function. Gentamicin pharmacokinetic parameters were determined in 44 PICU patients (0.8 month to 14 years old) from all available serum concentrations and doses by nonlinear least squares regression. Population pharmacokinetic parameter estimates were established from 27 of the PICU patients. Mean prediction error (ME) and mean absolute error (MAE) for 2 future sets of peak and trough gentamicin serum concentrations with the use of the population parameter estimates with and without feedback were evaluated in the remaining 17 patients. Mean clearance (+/- SD) and volume of distribution for all 44 patients were 0.123 +/- 0.041 liter/hour/kg and 0.424 +/- 0.116 liter/kg, respectively. Bayesian forecasting of the second set of peak and trough concentrations with feedback from the first set of peak and trough concentrations resulted in smaller bias (peak ME, -0.15 mg/liter; trough ME, 0.13 mg/liter) and better accuracy (peak MAE, 0.91 mg/liter; trough MAE, 0.28 mg/liter) compared with the population parameter estimates alone (peak ME, 0.4 mg/liter; trough ME, 0.28 mg/liter; peak MAE, 1.21 mg/liter; trough MAE, 0.57 mg/liter). This study indicates that gentamicin volume of distribution in PICU patients is larger than non-PICU literature values. The Bayesian program, with specific population parameter estimates for PICU patients, provides accurate initial and subsequent predictions of gentamicin serum concentrations.

Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance.

Pharmacokinetic data from 48 children who were taking valproic acid were analyzed by multiple stepwise linear regression. Children who were receiving enzyme-inducing antiepileptic drugs (n = 27) had greater (p < 0.01) clearances, elimination rates, and dosage requirements and greater (p < 0.05) variability in pharmacokinetic values than patients receiving monotherapy. Age and polytherapy explained most of the interpatient variability in total (r2 = 0.80; p < 0.001) and intrinsic (r2 = 0.77; p < 0.001) clearances and the elimination rate (r2 = 0.61; p < 0.002). Free fraction variability was related to valproate concentration and phenobarbital (r2 = 0.47; p < 0.001). Distribution volume variance was associated with free fraction (r2 = 0.48; p < 0.001). The effect of age and polytherapy on valproate clearance is primarily attributable to changes in metabolism rather than in protein binding. Valproic acid dosage requirements are greater and more variable for children who are receiving other enzyme-inducing antiepileptic drugs.

Prediction of gentamicin concentrations in neonates and infants using a Bayesian pharmacokinetic model.

This study retrospectively characterized population-based pharmacokinetic parameters for gentamicin in neonates and young infants, and evaluated the predictive performance of these parameters in a Bayesian forecasting program. Population parameter estimates were determined from the serum concentration-time data of 19 neonates and infants using a one-compartment open infusion model and nonlinear least-squares regression analysis. Univariate and multiple stepwise linear regression analyses were used to determine significant relationships between demographic characteristics and gentamicin pharmacokinetic parameters. Creatinine clearance and postnatal age were the most significant predictors of weight-standardized gentamicin clearance (model r2 = 0.86). The relationships between patient characteristics and population-based parameters were incorporated into the one-compartment Bayesian forecasting model. A second group of 17 neonates and infants receiving 35 courses of gentamicin therapy were used to evaluate the predictive performance of the population-based parameters and a Bayesian forecasting model. The population parameters provided accurate prediction of steady state gentamicin concentrations throughout multiple courses of therapy within the same patient. Bayesian forecasting further minimized the mean prediction error (bias) once a set of steady state peak and trough serum gentamicin concentrations became available (peak concentrations: -0.062 vs. -0.273 mg/l; trough concentrations: -0.006 vs. -0.161 mg/l). The mean absolute error (accuracy) was similar for the two sets of parameters. The observed accuracy of both the population parameters and Bayesian forecasting suggests that monitoring of serum gentamicin concentrations can be kept to minimum in neonates and infants.

Multilevel model to assess appropriateness of pediatric serum drug concentrations.

A multilevel model reviewing four assessment levels for pediatric serum drug concentrations was developed. Criteria for appropriate indication, sample collection, documentation, and utilization were based on therapeutic drug monitoring principles. The model was applied to 222 pediatric serum drug concentrations. Inadequate documentation was a major problem, but it occurred at a lower rate (37%) than previously reported. The rates of inappropriateness for indication (15%), sample collection (16%), and utilization (10%) were well within reported ranges but were significantly lower with pharmacy input. Overall, 48.2% of drug concentrations were inappropriate. Digoxin, phenobarbital, and aminoglycosides had the highest error rates. The annualized cost of inappropriate serum drug concentrations was $12,325. The described method allows for targeting of educational programs with defined areas for improvement. The findings of this study also support the involvement of clinical pharmacists in the therapeutic drug monitoring process.