Continuous Video Electroencephalographic (EEG) Monitoring for Electrographic Seizure Diagnosis in Neonates: A Single-Center Study.

The objective of this study was to determine the diagnostic yield of continuous video electroencephalographic (EEG) monitoring in critically ill neonates in the setting of a novel, university-based Neonatal Neurocritical Care Service. Patient demographic characteristics, indication for seizure monitoring, and presence of electrographic seizures were obtained by chart review. Among 595 patients cared for by the Neonatal Neurocritical Care Service, 400 (67%) received continuous video EEG. The median duration of continuous video EEG monitoring was 49 (interquartile range = 22-87) hours. Electrographic seizures were captured in 105 of 400 (26% of monitored patients) and of those, 25 of 105 (24%) had no clinical correlate. In addition, 52 of 400 subjects (13%) were monitored due to paroxysmal events concerning for seizures, but never had electrographic seizures. Continuous video EEG monitoring helped confirm or rule out ongoing seizures in more than one-third of the cases. This finding helps to support the use of continuous video EEG in critically ill neonates.

Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents.

Clindamycin is commonly prescribed to treat children with skin and skin-structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA)), yet little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. A one-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (l/h) = 13.7 × (weight/70)(0.75) × (PMA(3.1)/(43.6(3.1) + PMA(3.1))); V (l) = 61.8 × (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings support age-based dosing.

Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study.

Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a surrogate of mitochondrial function, were obtained in children 1.9 to 17.3 years of age (n = 52) who were undergoing treatment with VPA for seizure disorders. Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups. Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.

Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: an open-label, safety, efficacy, and pharmacokinetic study.

BACKGROUND: An increasing number of pediatric patients suffer from thrombotic events necessitating anticoagulation therapy including heparins. Some such patients develop heparin-induced thrombocytopenia (HIT) and thus require alternative anticoagulation. As such, studies evaluating the safety, efficacy, and dosing of alternative anticoagulants are required. PROCEDURE: In this multicenter, single arm, open-label study, 18 patients ≤ 16 years old received argatroban for either a suspicion of or being at risk for HIT, or other conditions requiring nonheparin anticoagulation. Endpoints included thrombosis, thromboembolic complications, and bleeding. RESULTS: Patients (ages, 1.6 weeks to 16 years) received argatroban usually for continuous anticoagulation (n = 13) or cardiac catheterization (n = 4). One catheterization patient received a 250 µg/kg bolus only; 17 patients received argatroban continuous infusion (median (range)) 1.1 (0.3-12) µg/kg/min (of whom four received a bolus) for 3.0 (0.1-13.8) days. In patients without bolus dosing, typically argatroban 1 µg/kg/min was initiated, with therapeutic activated partial thromboplastin times (aPTTs) (1.5-3× baseline) achieved within 7 hr. Within 30 days, thrombosis occurred in five patients (two during therapy). No one required amputation or died due to thrombosis during therapy. Two patients had major bleeding. Pharmacometric analyses demonstrated the optimal initial argatroban dose to be 0.75 µg/kg/min (if normal hepatic function), with dose reduction necessary in hepatic impairment. CONCLUSIONS: In pediatric patients requiring nonheparin anticoagulation, argatroban rapidly provides adequate levels of anticoagulation and is generally well tolerated. For continuous anticoagulation, argatroban 0.75 µg/kg/min (0.2 µg/kg/min in hepatic impairment), adjusted to achieve therapeutic aPTTs, is recommended.

Video-EEG monitoring in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.

BACKGROUND: Therapeutic hypothermia (TH) is becoming standard of care in newborns with hypoxic-ischemic encephalopathy (HIE). The prognostic value of the EEG and the incidence of seizures during TH are uncertain. OBJECTIVE: To describe evolution of EEG background and incidence of seizures during TH, and to identify EEG patterns predictive for MRI brain injury. METHODS: A total of 41 newborns with HIE underwent TH. Continuous video-EEG was performed during hypothermia and rewarming. EEG background and seizures were reported in a standardized manner. Newborns underwent MRI after rewarming. Sensitivity and specificity of EEG background for moderate to severe MRI brain injury was assessed at 6-hour intervals during TH and rewarming. RESULTS: EEG background improved in 49%, remained the same in 38%, and worsened in 13%. A normal EEG had a specificity of 100% upon initiation of monitoring and 93% at later time points. Burst suppression and extremely low voltage patterns held the greatest prognostic value only after 24 hours of monitoring, with a specificity of 81% at the beginning of cooling and 100% at later time points. A discontinuous pattern was not associated with adverse outcome in most patients (73%). Electrographic seizures occurred in 34% (14/41), and 10% (4/41) developed status epilepticus. Seizures had a clinical correlate in 57% (8/14) and were subclinical in 43% (6/14). CONCLUSIONS: Continuous video-EEG monitoring in newborns with HIE undergoing TH provides prognostic information about early MRI outcome and accurately identifies electrographic seizures, nearly half of which are subclinical.

Acetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose.

Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children presenting at eight pediatric hospitals with the chief complaint of APAP overdose. Two of the patients required liver transplantation, whereas all the others recovered spontaneously. Peak APAP adducts correlated with peak hepatic transaminase values, time-to-treatment with N-acetylcysteine (NAC), and risk determination per the Rumack-Matthews nomogram. A population pharmacokinetic analysis (NONMEM) was performed with post hoc empiric Bayesian estimates determined for the elimination rate constants (k(e)), elimination half-lives (t(1/2)), and maximum concentration of adducts (C(max)) of the subjects. The mean (+/-SD)k(e) and half-life were 0.486 +/- 0.084 days(-1) and 1.47+/- 0.30 days, respectively, and the C(max) was 1.2 (+/-2.92) nmol/ml serum. The model-derived, predicted adduct value at 48 h (Adduct 48) correlated with adductC(max), adduct T(max), Rumack-Matthews risk determination, peak aspartate aminotransferase (AST), and peak alanine aminotransferase (ALT). The pharmacokinetics and clinical correlates of APAP adducts in pediatric and adolescent patients with APAP overdose support the need for a further examination of the role of APAP adducts as clinically relevant and specific biomarkers of APAP toxicity.

Population pharmacokinetics of fluconazole in young infants.

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 . (weight/1)(0.75) . (BGA/26)(1.739) . (PNA/2)(0.237) . serum creatinine (SCRT)(-4.896) (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 . (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Emotional outcome of adolescents and young adults with early and continuously treated phenylketonuria.

OBJECTIVE: To assess the emotional functioning of adolescents and young adults with early and consistently treated phenylketonuria (PKU). METHODS: Twenty PKU-affected participants, ages 14-25, were compared with age-matched chronically ill (n = 17) and peer (n = 16) controls on a structured clinical interview, the Minnesota Multiphasic Personality Inventory, and the Tennessee Self-Concept Scale-2. Affected participants and nonparticipants were assessed using a multidomain assessment of functioning interview. RESULTS: There were no significant differences between groups for observable psychiatric disorders or emotional and functional symptoms. No significant differences were found in self-concept. Although there were no differences between groups for IQ or treatment variables, PKU-affected participants were more likely than nonparticipants to have sought help for psychological concerns. CONCLUSIONS: Results suggest that early-treated PKU-affected adolescents and young adults do not show a higher risk for psychological disturbance than appropriate controls.

Myelitis and ascending flaccid paralysis due to congenital toxoplasmosis.

A 4-week-old female newborn developed ascending flaccid paralysis and radiologic evidence of myelitis; the diagnosis of congenital toxoplasmosis was confirmed by the presence of Toxoplasma gondii-specific immunoglobulins in both mother and infant, and detection of Toxoplasma sequences in the infant's cerebrospinal fluid by polymerase chain reaction analysis. Treatment with pyrimethamine, sulfadiazine, and methylprednisolone resulted in improvement.

Elevation of serum interleukin 8 levels in acetaminophen overdose in children and adolescents.

BACKGROUND: Elevations of inflammatory cytokines have been reported in animal models of acetaminophen (INN, paracetamol) toxicity. In addition, interleukin 8, a chemokine, has been found to be elevated in toxin-associated hepatic disease (ie, acute alcoholic hepatitis). The purpose of this study was to measure serum cytokine levels in children and adolescents with acetaminophen overdose and to evaluate relationships between cytokine elevation and hepatotoxicity. METHODS: Serum levels of tumor necrosis factor alpha, interleukin 1beta, interleukin 6, interleukin 8, and interleukin 10 were measured by ELISA in children and adolescents (n = 35) with acetaminophen overdose. Peak cytokine levels were examined relative to biochemical evidence of hepatocellular injury, nomogram risk assessment, and prothrombin time. RESULTS: Five patients had aspartate aminotransferase or alanine aminotransferase levels >1000 IU/L, and 4 patients had aspartate aminotransferase or alanine aminotransferase levels > or =100 IU/L and < or =1000 IU/L. No elevations of tumor necrosis factor alpha or interleukin 1beta were detected. Peak interleukin 8, but not interleukin 6 or interleukin 10, correlated with hepatotoxicity (Mann-Whitney exact test, P <.001). The peak interleukin 8 level was greater in patients at high risk by the nomogram combined with those presenting at >15 hours, as compared with other patients (Mann-Whitney U test, P <.01). The interleukin 8 level peaked before aspartate aminotransferase or alanine aminotransferase in 5 of the 9 patients with hepatotoxicity. In addition, interleukin 8 concentrations of >20 pg/mL were associated with peak prothrombin time values (Mann-Whitney exact test, P <.015). CONCLUSIONS: Interleukin 8 elevation in patients with acetaminophen hepatotoxicity corresponds with other common clinical measures that are predictive of hepatocellular injury. Further study is warranted to evaluate possible mechanistic relationships between inflammatory cytokines and acetaminophen hepatotoxicity in children and adults.

Measurement of acetaminophen-protein adducts in children and adolescents with acetaminophen overdoses. .

Acetaminophen-protein adducts are biomarkers of acetaminophen toxicity present in the centrilobular region of the liver of laboratory animals following the administration of toxic doses of acetaminophen. These biomarkers are highly specific for acetaminophen-induced hepatic injury and correlate with hepatic transaminase elevation. The objective of this prospective, multicenter study was to evaluate the clinical application of the measurement of acetaminophen-protein adducts in pediatric acetaminophen overdose patients. Serum samples were obtained from 51 children and adolescents with acetaminophen overdose at the time of routine blood sampling for clinical monitoring. Six subjects developed "severe" hepatotoxicity (transaminase elevation > 1,000 IU/L), and 6 subjects had transaminase elevation of 100 to 1,000 IU/L. Acetaminophen-protein adducts were detected in the serum of only 1 study subject, a patient with marked transaminase elevation (> 6,000 IU/L) and high risk for the development of hepatotoxicity according to the Rumack nomogram. While this study provides further support for the occurrence of covalent binding of acetaminophen to hepatic protein in humans following acetaminophen overdose, the detection of acetaminophen-protein adducts in serum with the current methodology requires significant biochemical evidence of hepatocellular injury.

Radiovisiography in the detection of periapical lesions.

The periapical areas of 16 teeth from 6 human mandibular jaw specimens were randomly examined by 3 observers using conventional radiography with Kodak E-speed film and radiovisiography (with variable contrast and with fixed contrast). Each periapical area was examined preoperatively and after #2, #4, #6, and #8 sized bur periapical lesions were created in the cortical bone. The three radiographic methods were compared by repeated-measures ANOVA of the accuracy scores for the 16 periapical lesions. Accuracy increased with size of lesion, but did not vary by method. Repeated-measures ANOVA of the accuracy scores of only the smallest and no lesion condition showed that conventional radiography and radiovisiography (variable contrast) have opposite strengths. Conventional radiography tended to be more accurate in the no lesion condition, whereas radiovisiography using variable contrast was somewhat more accurate in the smallest lesion condition. The accuracy of radiovisiography with fixed contrast was not significantly different from the other two methods.

Prognostic value of pre- and postoperative cardiac troponin I measurement in children having cardiac surgery.

The objective of this study was to determine if perioperative elevation of cardiac troponin I (cTnI) predicts mortality in infants and children after surgical correction of congenital heart defects. One hundred infants and children having open heart surgery were studied. Blood samples for cTnI analysis were collected before cardiopulmonary bypass (CPB) and at 4, 8, 12, and 24 h after initiation of CPB. Demographic information, cardiac defect, repair performed, duration of CPB, complications, and outcome were recorded. Cardiac defects were categorized as atrial septal defect (ASD), ventricular septal defect (VSD), hypoplastic left heart syndrome (HLHS), complex, and "other." Baseline cTnI was significantly lower in survivors (mean 0.42 ng/ml, median 0.35 ng/ml) than in nonsurvivors (mean 1.89, median 1.30), p = 0.0001. Baseline cTnI was significantly higher in the HLHS group (mean 1.47, median 1.10) than in all other subgroups (mean 0.62, median 0.35), p 125 ng/ml compared to survivors (2 of 90). Within cardiac defect subgroups, 4 h cTnI was significantly higher in the complex group (mean = 53.51, median = 32.30) than in the ASD (mean = 23.84, median = 19.85) and other (mean = 21.59, median 21.50) subgroups. Perioperative measurement of cTnI identifies children within specific cardiac defect subgroups at risk of mortality after cardiac surgery. We speculate that detection of myocardial injury may decrease mortality and morbidity in children with complicated congenital cardiac lesions by leading to improvements in perioperative management.

Review: emotional and behavioral functioning in phenylketonuria.

OBJECTIVE: To examine 17 studies of the psychological sequelae of early-treated phenylketonuria (PKU) with emphasis on the impact of dietary control on functioning. Two questions are addressed: (1) What is the typical psychological profile associated with PKU? (2) Is emotional and behavioral disturbance more prevalent in PKU-affected individuals compared to appropriate controls? METHOD: Computerized searches of PsycINFO identified studies using behavioral, personality, and diagnostic measures. RESULTS: Findings converge upon a profile including attentional difficulties, depression, anxiety, and low self-esteem. Methodological constraints limit conclusions regarding the nature and severity of observed difficulties. A single study has used comparison groups appropriate for the simultaneous examination of the questions posed (Waisbren and Levy, 1991). CONCLUSIONS: We discuss results using a biopsychosocial framework, addressing the factors and processes that may influence emotional and behavioral functioning in this neurodevelopmental disorder. We outline potential lines of new investigation that address critical methodological factors.

Super-EBA as an endodontic apical plug.

Forty extracted human single-rooted teeth were sequentially instrumented with nickel-titanium rotary files to a size 0.36 mm at the working length. Ten teeth were randomly assigned to the two control groups. The other 30 teeth were randomly divided into three groups and were obturated by a 5-mm apical plug of either Super-EBA, IRM, or laterally condensed gutta-percha and Roth's sealer. After 2 days, and at 1 month, the samples were tested for microleakage by the fluid filtration system under 15 psi. The negative controls were used to consider the time that it took the fluid filtration system to stabilize. A one-way analysis of variance showed that, at 1 month post obturation, there was no statistical difference in the ability of the three materials to seal the apex from coronal microleakage. However, at 2 days, Super-EBA gave a significantly better seal than IRM or laterally condensed gutta-percha and sealer.

The cloning expression and tissue distribution of human PP2Cbeta.

We have cloned a novel PP2Cbeta isoform from a human liver cDNA library which codes for a protein homologous to other mammalian PP2Cbetas at the N-terminus but with an extended C-terminus that is unique amongst the PP2Cs. The protein expressed in E. coli is indistinguishable from human recombinant PP2Calpha in its cation dependence and insensitivity to okadaic acid. Northern blot analysis of PP2Cbeta along with that of PP2Calpha shows that human PP2Cs are widely expressed and are most abundant in heart and skeletal muscle.

Evaluating IAIMS at Yale: information access.

OBJECTIVE: To evaluate use of information resources during the first year of IAIMS implementation at the Yale-New Haven Medical Center. The evaluation asked: (1) Which information resources are being used? (2) Who uses information resources? (3) Where are information resources used? (4) Are multiple sources of information being integrated? DESIGN: Measures included monthly usage data for resources delivered network-wide, in the Medical Library, and in the Hospital; online surveys of library workstation users; an annual survey of a random, stratified sample of Medical Center faculty, postdoctoral trainees, students, nurses, residents, and managerial and professional staff; and user comments. RESULTS: Eighty-three percent of the Medical Center community use networked information resources, and use of resources is increasing. Both status (faculty, student, nurse, etc.) and mission (teaching, research, patient care) affect use of individual resources. Eighty-eight percent of people use computers in more than one location, and increases in usage of traditional library resources such as MEDLINE are due to increased access from outside the Library. Both survey and usage data suggest that people are using multiple resources during the same information seeking session. CONCLUSIONS: Almost all of the Medical Center community is using networked information resources in more settings. It is necessary to support increased demand for information access from remote locations and to specific populations, such as nurses. People are integrating information from multiple sources, but true integration within information systems is just beginning. Other institutions are advised to incorporate pragmatic evaluation into their IAIMS activities and to share evaluation results with decision-makers.

Biochemical characterization and deletion analysis of recombinant human protein phosphatase 2C alpha.

The use of protein phosphatase inhibitors has been instrumental in defining the intracellular roles of protein phosphatase 1 (PP1), PP2A and PP2B. Identification of the role of PP2C in vivo has been hampered, in part, by the unavailability of specific inhibitors. In order to facilitate the identification of novel and specific inhibitors of PP2C by random screening of compounds, and to further characterize this enzyme at the molecular level by site-directed mutagenesis and X-ray crystallography, we have expressed active recombinant human PP2C alpha (rPP2C alpha) in Escherichia coli. Biochemical characterization of rPP2C alpha showed that it could hydrolyse p-nitrophenyl phosphate (pNPP) although, in contrast with native PP2C, this was not stimulated by Mg2+. As with native PP2C, okadaic acid failed to inhibit rPP2C alpha, whereas 50 mM NaF dramatically inhibited its activity. An alignment of the amino acid sequence of AMP-activated protein kinase (AMPK) with those of other serine/threonine protein kinases around the regulatory phosphorylation site (subdomains VII-VIII) revealed a high degree of conservation. Phosphopeptides derived from this region of AMPK and containing the almost invariant threonine (Thr172 in AMPK) were found to be good substrates for rPP2C alpha. We also showed that rPP2C alpha can inactivate AMPK, but only in the presence of Mg2+. To define the regions of PP2C alpha important for catalytic activity, we expressed a number of truncated proteins based on the sequence and proposed domain structure of the PP2C alpha homologue from Paramecium tetraurelia. Deletion of 75 residues (9 kDa) from the C-terminus appeared to have little effect on the catalytic activity using pNPP, phosphopeptides or AMPK as substrates. This suggests that the residues important in catalysis lie elsewhere in the protein. A further deletion of the C-terminus led to a completely inactive and very poorly soluble protein.

Analysis of the variability in the pharmacokinetics and pharmacodynamics of bumetanide in critically ill infants.

OBJECTIVES: Account for the interindividual variability in the pharmacokinetics and pharmacodynamics of bumetanide after intravenous administration of single doses to critically ill infants. METHODS: This prospective open-label study was carried out in the pediatric intensive care unit of a university-based children's hospital. Fifty-three volume-overloaded critically ill infants (age range, 4 days to 6 months) were divided into two groups: those with heart disease (31 infants) and those with lung disease (22 infants). Each patient received a single intravenous bolus dose of bumetanide. Doses, selected in sequential order, ranged from 0.005 to 0.100 mg/kg. Age was used as a continuous variable to determine its effects on the variability in the pharmacokinetics and pharmacodynamics of bumetanide. Hierarchical multiple regression analyses were used to assess the effects of age, disease, and other drugs on the variability in the effects of bumetanide. RESULTS: Total clearance, renal clearance, and nonrenal clearance of bumetanide all increased with age (p < 0.05), but the ratio of renal clearance to total clearance remained constant at about 0.4. Half-life and mean residence time decreased markedly in the first month of life (p < 0.05). Bumetanide excretion rate normalized for dose also increased with increasing age. Patients with lung disease exhibited a significantly greater clearance and shorter half-life (p < 0.05) than those with heart disease, whereas volume of distribution was similar in both groups. The primary determinant of bumetanide excretion rate was the administered dose (73%). Dose-response curves for urine flow rate and electrolyte excretion were similar between disease groups. The time course of the effect of bumetanide excretion rate on pharmacodynamics responses was similar between disease groups, as was the duration of the diuretic effect. CONCLUSIONS: The pharmacokinetics of bumetanide were influenced significantly by age and disease. Differences in pharmacokinetics between patients with lung and heart disease were primarily due to differences in total clearance. The administered dose of bumetanide and age were positive determinants of bumetanide excretion rate and pharmacodynamic responses. Pharmacodynamic responses as a function of bumetanide excretion rate were not significantly different between disease groups.