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Obesity is an increasingly alarming public health threat, with nearly 20% of children classified as obese in the United States today. Children with obesity are commonly prescribed the opioids fentanyl and methadone, and accurate dosing is critical to reducing the risk of serious adverse events associated with overexposure. However, pharmacokinetic studies in children with obesity are challenging to conduct, so there is limited information to guide fentanyl and methadone dosing in these children. To address this clinical knowledge gap, physiologically-based pharmacokinetic models of fentanyl and methadone were developed in adults and scaled to children with and without obesity to explore the interplay of obesity, age, and pharmacogenomics. These models included key obesity-induced changes in physiology and pharmacogenomic effects. Model predictions captured observed concentrations in children with obesity well, with an overall average fold error of 0.72 and 1.08 for fentanyl and methadone, respectively. Model simulations support a reduced fentanyl dose (1 vs. 2 μg/kg/h) starting at an earlier age (6 years) in virtual children with obesity, highlighting the importance of considering both age and obesity status when selecting an infusion rate most likely to achieve steady-state concentrations within the target range. Methadone dosing simulations highlight the importance of considering genotype in addition to obesity status when possible, as cytochrome P450 (CYP)2B6*6/*6 virtual children with obesity required half the dose to match the exposure of wildtype children without obesity. This physiologically-based pharmacokinetic modeling approach can be applied to explore dosing of other critical drugs in children with obesity., (© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background and Objectives: The Best Pharmaceuticals for Children Act (BPCA) incentivizes the study of on-patent medicines in children and mandates that the National Institutes of Health sponsor research on off-patent drugs important to pediatric therapeutics. Failing to enroll cohorts that reflect the pediatric population at large restricts the generalizability of such studies. In this investigation, we evaluate racial and ethnic minority representation among participants enrolled in BPCA-sponsored studies., Methods: Data were obtained for all participants enrolled in 33 federally funded studies of drugs and devices conducted from 2008 through June 2020. Observed racial and ethnic distributions were compared with expected distributions by sampling Census data at the same geographic frequency as in the studies. Racial and ethnic enrollment was examined by demography, geography, study type, study burden, and expected bias. Standard descriptive statistics, χ 2 , generalized linear models, and linear regression were applied., Results: A total of 10 918 participants (51% male, 6.6 ± 8.2 years) were enrolled across 46 US states and 4 countries. Studies ranged from treatment outcome reviews to randomized, placebo-controlled trials. Minority enrollment was comparable to, or higher than, expected (+0.1% to +2.6%) for all groups except Asian Americans (-3.7%, P < .001). American Indian and Alaskan Native and multiracial enrollment significantly increased over the evaluation period ( P < .01). There were no significant differences in racial distribution as a function of age or sex, although differences were observed on the basis of geography, study type, and study burden., Conclusions and Relevance: This study revealed no evidence of racial and ethnic bias in enrollment for pediatric studies conducted with funding from BPCA, fulfilling the legislation's expectation to ensure adequate representation of all children., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Abdel-Rahman, Ms Delmore, and Drs Hornik, Paul, Sullivan, Wade, and Zimmerman serve as members of the steering committee for the Pediatric Trials Network, which receives Best Pharmaceuticals for Children Act funding from the Eunice Kennedy Shriver National Institute for Child Health and Human Development. Dr Benjamin serves as the PI of the Pediatric Trials Network. At the time of writing Dr Sharma was employed by the Best Pharmaceuticals for Children Act data coordinating center., (Copyright © 2021 by the American Academy of Pediatrics.)

Metoclopramide is commonly used for gastroesophageal reflux. The aims of the present study were to develop a pediatric population pharmacokinetic (PopPK) model, which was applied to simulate the metoclopramide exposure following dosing used in clinical practice. Opportunistic pharmacokinetic data were collected from pediatric patients receiving enteral or parenteral metoclopramide per standard of care and these data were simultaneously fitted using NONMEM. Allometric scaling with body weight was included a priori in the model. Using the final model, the steady-state maximum concentrations (C ss,max ) and the area under the metoclopramide plasma concentration-time curve at steady state from 0 to 6 hours (AUC ss,0-6h ) were simulated following 0.1 or 0.15 mg/kg orally every 6 hours in virtual patients, and compared with previously reported ranges associated with toxicity or the efficacy for gastroesophageal reflux in infants. A two-compartment model with first-order absorption best characterized 87 concentration measurements from 50 patients (median [range] postnatal age of 8.89 years [0.01-19.13]). There were 20 infants (≤ 2 years), 9 children (2 years to age ≤ 12 years), and 21 adolescents (> 12 years). Body weight was the only covariate included in the final model. For > 75% of virtual patients, simulated C ss,max and AUC ss,0-6h estimates were within the range associated with efficacy for gastroesophageal reflux in infants; however, slightly lower exposures were predicted in virtual patients < 2 years. Our study suggests that a metoclopramide enteral dose of 0.1 mg/kg every 6 hours, which was previously recommended for pediatric patients, results in simulated exposure generally within suggested ranges for the treatment of gastroesophageal reflux., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society of Clinical Pharmacology and Therapeutics.)

Background: Metronidazole is frequently used off-label in infants with complicated intra-abdominal infections (cIAI) to provide coverage against anaerobic organisms, but its safety and efficacy in this indication are unknown., Methods: In the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections open-label multicenter trial infants ≥34 weeks gestation at birth and <121 days postnatal age with cIAIs were administered metronidazole as part of multimodal therapy. Metronidazole safety was evaluated by reporting of adverse events (AEs) and safety events of special interest. Cure from disease was determined by blood cultures and a clinical cure score >4. A blinded adjudication committee reviewed all safety events of special interest., Results: Fifty-five infants were included, median gestational age was 36 weeks (range: 34-41) and postnatal age was 7 days (0-63). The most common additional antibiotics received included gentamicin, piperacillin-tazobactam, ampicillin and vancomycin. Only one AE, a candidal rash, was identified to be potentially caused by metronidazole administration. One infant died of cardiopulmonary failure, which was deemed unrelated to metronidazole. The most common events of special interest included feeding intolerance in 18 (33%) infants, and exploratory laparotomy in 10 (18%) requiring intestinal anastomosis in 7 (13%) infants. There was 1 (2%) intestinal stricture. Fifty-three infants (96%) achieved overall therapeutic success, 54 (98%) were alive through 30 days post-study therapy, and 54 (98%) had 30-day clinical cure score >4., Conclusions: In a cohort of late pre-term and term infants with cIAIs, combination antibiotic therapy that included metronidazole was safe, and therapeutic success was high.

Background: Weight is critical for the medical management of infants; however, scales can be unavailable or inaccessible in some practice settings. We recently developed and validated a robust infant weight estimation method based on chest circumference (CC) and head circumference (HC). This study was designed to determine the human factors (HF) experience with, and predictive performance of, an infant weight estimation device that implements this method., Methods: Prospective, multi-center, observational, masked study of 486 preterm and term infants (0-90 days) assessed by 15 raters. Raters measured the infant using calibrated scales/measures and masked versions of the device. Raters also evaluated critical tasks associated with device use. Mean error (ME) and mean percentage error (MPE) were used to assess predictive performance., Result: Among 486 infants enrolled (36.8 ± 4.0 weeks gestational age, 31.5 ± 28.6 days postnatal age), predicted weight correlated highly with actual weight (r = 0.97, ME: - 69 ± 257 g, MPE: - 1.3 ± 6.9%). Predicted weight was within 10 and 15% of actual weight in 86 and 99%, of infants. HF errors were low, 0.1-0.8% depending on task. In all cases raters were confident or very confident in their measurements., Conclusion: The device was statistically equivalent to the method on which it was based and approximated weight with acceptable variance from the true weight. HF data suggest the device is easy to use. This device can be used to estimate weight in infants when calibrated scales are impractical or unavailable.

Ketamine is an N-methyl D-aspartate receptor antagonist used off-label to facilitate dissociative anesthesia in children undergoing invasive procedures. Available for both intravenous and intramuscular administration, ketamine is commonly used when vascular access is limited. Pharmacokinetic (PK) data in children are sparse, and the bioavailability of intramuscular ketamine in children is unknown. We performed 2 prospective PK studies of ketamine in children receiving either intramuscular or intravenous ketamine and combined the data to develop a pediatric population PK model using nonlinear mixed-effects methods. We applied our model by performing dosing simulations targeting plasma concentrations previously associated with analgesia (>100 ng/mL) and anesthesia awakening (750 ng/mL). A total of 113 children (50 intramuscular and 63 intravenous ketamine) with a median age of 3.3 years (range 0.02 to 17.6 years), and median weight of 14 kg (2.4 to 176.1) contributed 275 plasma samples (149 after intramuscular, 126 after intravenous ketamine). A 2-compartment model with first-order absorption following intramuscular administration and first-order elimination described the data best. Allometrically scaled weight was included in the base model for central and peripheral volume of distribution (exponent 1) and for clearance and intercompartmental clearance (exponent 0.75). Model-estimated bioavailability of intramuscular ketamine was 41%. Dosing simulations suggest that doses of 2 mg/kg intravenously and 8 mg/kg or 6 mg/kg intramuscularly, depending on age, provide adequate sedation (plasma ketamine concentrations >750 ng/mL) for procedures lasting up to 20 minutes., (© 2018, The American College of Clinical Pharmacology.)

Background: Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated., Methods: An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches., Results: A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CONCPlasma (eCONCPlasma) was derived using (CONCDBS - 3.223)/0.51. The median bias and geometric mean ratio improved to -11% and 0.88 (Wilcoxon signed-rank test, P < 0.001), respectively, when comparing eCONCPlasma to CONCPlasma. Furthermore, using pop-PK modeling, the median bias (interquartile range) for clearance and individual predicted concentrations improved to 8% (-11 to 50) and -8% (-34 to 11), respectively, when eCONCPlasma was used., Conclusions: After transformation, DBS sampling accurately predicted ampicillin exposure in neonates.

Weight is the foremost marker of health outcomes in infants; however, the majority of community workers and health care providers in remote, resource-constrained settings have limited access to functional scales. This study develops and validates a simple weight estimation strategy for infants that addresses the limitations of current approaches. Circumferential and segmental anthropometric measures were evaluated for their relationship to infant weight and length. Data derived from 2097 US infants (n = 1681 for model development, n = 416 for validation). Statistical and practical considerations informed final measurement selection. Head circumference and chest circumference demonstrated the best correlations with weight ( r = 0.89) and length ( r = 0.94 and 0.93), and were among the most reproducible as reflected by intraclass correlation coefficients (>0.98). The head circumference and chest circumference combination offered better goodness-of-fit and smaller limits of agreement than did either measure alone. The final model predicted weight within 10% and 15% of actual for 84% and 94% of infants, respectively, with no bias for postnatal age ( P = .76), gestational age ( P = .10), and sex ( P = .25). The model requires simple summation to generate a weight estimate and can be embodied as a low-cost, paper-based device., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children. Separate population PK models were developed for TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/ F ) and volume of distribution ( V / F ). Both TMP and SMX CL/ F increased with age. In addition, TMP and SMX CL/ F were inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in >90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to <21 years and 0 to <6 years of age, respectively, and was optimal for bacteria with an MIC of up to 1 mg/liter., (Copyright © 2017 American Society for Microbiology.)

Background: Anthropometric data prove valuable for screening and monitoring various medical conditions. In young infants, however, only weight, length and head circumference are represented in publicly accessible databases., Aim: To characterise length and circumferential measures in pre-term and full-term infants up to 90 days post-natal., Subjects and Methods: In eight US medical centres, trained raters recorded humeral, ulnar, femoral, tibial and fibular lengths along with mid-upper arm, mid-thigh, chest, abdominal and neck circumference. Data were pooled by post-menstrual age into 1-week intervals and population curves created using the lambda, mu and sigma (LMS) method. Goodness-of-fit was assessed by examining de-trended quantile-quantile plots, Q statistics and fitted centiles overlaid on empirical centiles., Results: In total, 2097 infants were enrolled in this study with a mean ± SD gestational age and post-natal age of 37.1 ± 3.3 weeks and 27.3 ± 25.3 days, respectively. A re-scale option was used to describe all curves. The resultant models reliably characterised anthropometric measures from 33-52 weeks PMA, with less certainty at the extremes (27-55 weeks)., Conclusion: The population curves generated under this investigation expand existing reference data on a comprehensive set of anthropometric traits in infants through the first 90 days post-natal.

Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.)., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: Trimethoprim-sulfamethoxazole (TMP-SMX) is an antimicrobial drug combination commonly prescribed in children and adults. The study objectives were to validate and apply an HPLC-MS/MS method to quantify TMP-SMX in dried plasma spots (DPS) and dried urine spots (DUS), and perform a comparability analysis with liquid matrices., Results: For TMP the validated range was 100-50,000 ng/ml for DPS and 500-250,000 ng/ml for DUS; for SMX, the validated range was 1000-500,000 ng/ml for both DPS and DUS. Good agreement was noted between DPS/DUS and liquid plasma and urine samples for TMP, while only modest agreement was observed for SMX in both matrices., Conclusion: A precise, accurate and reproducible method was developed to quantify TMP-SMX in DPS and DUS samples., Competing Interests: Financial & competing interest disclosure This work was funded under National Institute of Child Health and Human Development (NICHD) contract HHSN201000003I for the Pediatric Trials Network (PI: Benjamin) and HHSN27500006 (PI: Melloni, Cohen-Wolkowiez) for the Pharmacokinetics of Understudied Drugs Administered to Children per Standard of Care Study (POPS; protocol NICHD-2011-POP01). Research reported in this publication also was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number UL1TR001117. The assay measuring TMP-SMX concentrations was performed at OpAns Laboratory (Durham, NC, USA). D Gonzalez is funded by training grant T32GM086330 from the National Institute of General Medical Sciences (NIGMS). D K Benjamin Jr receives support from the US government for his work in pediatric and neonatal clinical pharmacology (2K24HD058735–06, UL1TR001117, NICHD contract HHSN275201000003I and NIAID contract HHSN2722015000061); he also receives research support from Cempra Pharmaceuticals (subaward to HHSO100201300009C) for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). M Cohen-Wolkowiez receives support for research from the NIH (1R01-HD076676–01A1), the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), the National Institute of Allergy and Infectious Disease (HHSN272201500006I and HHSN272201300017I), the National Institute for Child Health and Human Development of the NIH (HHSN275201000003I), the FDA (1U01FD004858–01), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org) and from industry (CardioDx and Durata Therapeutics) for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp). The remaining authors have no funding to disclose. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors thank A McMillan for her editorial assistance. A McMillan was funded by HHSN27500006 (PI: Melloni, Cohen-Wolkowiez).

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.

Although ampicillin is the most commonly used drug in neonates, developmental pharmacokinetic (PK) data to guide dosing are lacking. Ampicillin is primarily renally eliminated, and developmental changes are expected to influence PK. We conducted an open-label, multicenter, opportunistic, prospective PK study of ampicillin in neonates stratified by gestational age (GA) (≤ 34 or >34 weeks) and postnatal age (PNA) (≤ 7 or >7 days). Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effects modeling in NONMEM 7.2. Monte Carlo simulations were conducted to determine the probability of target attainment for the time in which the total steady-state ampicillin concentrations remained above the MIC (T>MIC) for 50%, 75%, and 100% of the dosing interval. A total of 142 PK samples from 73 neonates were analyzed (median [range] GA, 36 [24 to 41] weeks; PNA, 5 [0 to 25] days). The median ampicillin dose was 200 (100 to 350) mg/kg/day. Postmenstrual age and serum creatinine were covariates for ampicillin clearance (CL). A simplified dosing regimen of 50 mg/kg every 12 h for GA of ≤ 34 weeks and PNA of ≤ 7 days, 75 mg/kg every 12 h for GA of ≤ 34 weeks and PNA of ≥ 8 and ≤ 28 days, and 50 mg/kg every 8 h for GA of >34 weeks and PNA of ≤ 28 days achieved the prespecified surrogate efficacy target in 90% of simulated subjects. Ampicillin CL was associated with neonatal development. A simplified dosing regimen stratified by GA and PNA achieves the desired surrogate therapeutic target in the vast majority of neonates., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Objective: We changed from ampicillin and gentamicin (AG) to piperacillin-tazobactam (PT) for routine treatment of suspected early-onset sepsis. The rationale for this change included ototoxic and renal toxic effects of gentamicin, resistance to gentamicin in late-onset infections and emergence of ampicillin resistant Escherichia coli. A before and after study was designed before the start of PT administration to monitor whether PT was associated with altered outcomes within the 501 to 1500 g birth weight (Very Low Birth Weight) population., Method: Both unmatched and matched comparisons of AG (2007 to 2009) and PT (2010 to 2011) exposed infants are reported. Cohorts were evaluated for initial effectiveness for congenital infections, subsequent morbidities and mortality., Results: Data from 714 patients were collected (499 AG and 215 PT in the unmatched and 301 AG and 183 PT in the matched cohorts). No significant differences in demographics or initial Apgar scores were noted in the unmatched or matched comparisons. There were significant differences in many of the outcomes of interest in both the matched and unmatched comparisons including less necrotizing enterocolitis (NEC) and less diaper rash with PT versus AG. The only adverse finding with PT was a small, but statistically significant elevation in alkaline phosphatase., Conclusions: Use of PT as the initial empiric antibiotic for very low birth weight infants was not associated with adverse microbiological outcomes. There was no increase in major morbidities. Although outcomes were superior in ≤ 1500 g infants treated with PT when compared with AG, the study design does not allow us to conclude that others will see a reduction in NEC or diaper rash if they implement this alternative.

Objective: To establish the reproducibility of a published observation by Lubetzky et al. that infants affected by retinopathy of prematurity (ROP) had higher absolute nucleated red blood cell (aNRBC) counts than those unaffected. The authors suggested that infants exposed to intrauterine hypoxia are at higher risk for ROP. We attempted to verify this reported relationship of ROP with the aNRBCs at birth and hypothesized that infants with ROP ≥ stage 2 have higher aNRBCs at birth., Study Design: We report a retrospective 1:1 case matched analysis where cases had a diagnosis of grade II ROP or worse and matching infants had confirmed stage I or no ROP. Eligible infants had birth weights of 501 to 1500 g and were discharged alive from 1st January 2000 to 31st December 2008. Wilcoxon's signed rank test was performed for continuous comparisons. This study was approved by two local Institutional Review Boards., Result: In all, 66 matched pairs were analyzed. When comparing aNRBCs there was no statistically significant relationship (w=-0.265, P=0.791) between the ROP affected group (M=4550, s.d.=7342) and the unaffected group (M=5287, s.d.=6524)., Conclusion: We are unable to support the previously reported relationship of aNRBCs with ROP. Our population was three times larger, had higher aNRBCs and less retinopathy than previously reported. A biological principle of cause and effect or predisposition to ROP as reflected by aNRBCs should have been easier for us to demonstrate, if it existed.

A multi-center four-hourly sampling of many tissues for 7 days (00:00 on April 5-20:00 to April 11, 2004), on rats standardized for 1 month in two rooms on antiphasic lighting regimens happened to start on the day after the second extremum of a moderate double magnetic storm gauged by the planetary geomagnetic Kp index (which at each extremum reached 6.3 international [arbitrary] units) and by an equatorial index Dst falling to -112 and -81 nT, respectively, the latter on the first day of the sampling. Neuroendocrine chronomes (specifically circadian time structures) differed during magnetically affected and quiet days. The circadian melatonin rhythm had a lower MESOR and lower circadian amplitude and tended to advance in acrophase, while the MESOR and amplitude of the hypothalamic circadian melatonin rhythm were higher during the days with the storm. The circadian parameters of circulating corticosterone were more labile during the days including the storm than during the last three quiet days. Feedsidewards within the pineal-hypothalamic-adrenocortical network constitute a mechanism underlying physiological and probably also pathological associations of the brain and heart with magnetic storms. Investigators in many fields can gain from at least recording calendar dates in any publication so that freely available information on geomagnetic, solar and other physical environmental activity can be looked up. In planning studies and before starting, one may gain from consulting forecasts and the highly reliable nowcasts, respectively.

Objective: To evaluate the feasibility and safety of administering surfactant into the nasopharynx during delivery, thus permitting the baby to aspirate the solution into the fluid-filled airway as an air-fluid interface is established. This process avoids the endotracheal intubation (ETI) and positive pressure ventilation (PPV) usually associated with prophylaxis, thus avoiding the pulmonary barotrauma associated with the conventional method of surfactant administration., Study Design: In all, 23 neonates weighing 560 to 1804 g and born at 27 to 30 weeks had their nasopharyngeal airways suctioned and then 3.0-4.5 ml Infasurf instilled into the nasopharynx before delivery of the shoulders. Continuous positive airway pressure (CPAP) of 10 cmH(2)O was administered by mask as the babies initiated breathing. Nasal CPAP at 6 cmH(2)O was then continued for a minimum of 48 hours., Results: In all, 13 of 15 babies delivered vaginally were weaned quickly to room air and required no further surfactant or endotracheal intubation for RDS. Five of eight babies delivered by C-section required subsequent endotracheal intubation soon after birth and two received subsequent endotracheal tube surfactant., Conclusion: Nasopharyngeal surfactant instillation at birth appears to be relatively safe and simple to accomplish, especially for vaginal births. A large randomized clinical trial will be required to determine the efficacy of this technique when compared to prophylaxis by endotracheal intubation and to nCPAP alone.

Objective: Part of the process of deriving and refining the CARE (communication, accountability, respect, empowerment) focus group's potentially better practices (PBPs) for multidisciplinary teamwork was to evaluate and experience the PBPs through implementation., Methods: The 4 neonatal intensive care units (NICUs) in the CARE focus group each worked with implementation of the PBPs. The choice of initial PBP and method of implementation was left up to each NICU's core team., Results: The experience of each of the PBPs that is reported was selected from only 1 of the NICUs. These are summarized and described in a plan-do-study-act type of format., Conclusions: There was no ideal PBP with which to start. The intertwined nature of all of the PBPs provided additional opportunities to implement other PBPs. A change seemed to be a matter first of vocabulary, then of tentative acceptance, followed by gradual integration into the culture. Change was facilitated when there was acknowledgment of a need to do things differently by the NICU leadership. Although the validity of the PBPs and their importance in cultural change have yet to be confirmed, once there was a persisting intent to change, the makeup of the NICU culture moved to embrace change as part of its culture.

This review provides evidence that the bioengineering community needs to develop cost-effective, fully unobtrusive, truly ambulatory instrumentation for the surveillance of blood pressure and heart rate. With available instrumentation, we document a disease risk syndrome, circadian blood pressure overswinging (CHAT, short for circadian hyper-amplitude-tension). Circadian hyper-amplitude-tension is defined as a week-long overall increase in the circadian amplitude or otherwise-measured circadian variability of blood pressure above a mapped threshold, corresponding to the upper 95% prediction limit of clinically healthy peers of the corresponding gender and age. A consistently reduced heart rate variability, gauged by a circadian standard deviation below the lower 5% prediction limit of peers of the corresponding gender and age, is an index of a separate yet additive major risk, a deficient heart rate variability (DHRV). The circadian amplitude, a measure of the extent of reproducible variability within a day, is obtained by linear curve-fitting, which yields added parameters: a midline-estimating statistic of rhythm, the MESOR (a time structure or chronome-adjusted mean), the circadian acrophase, a measure of timing of overall high values recurring in each cycle, and the amplitudes and acrophases of the 12-hour (and higher order) harmonic(s) of the circadian variation that, with the characteristics of the fundamental 24-hour component, describe the circadian waveform. The MESOR is a more precise and more accurate estimate of location than the arithmetic mean. The major risks associated with CHAT and/or DHRV have been documented by measurements of blood pressure and heart rate at 1-hour or shorter intervals for 48 hours on populations of several hundred people, but these risks are to be assessed in a 7-day/24-hour record in individuals before a physical examination, for the following reasons. (1) The average derived from an around-the-clock series of blood pressure measurements, computed as its MESOR, the proven etiopathogenetic factor of catastrophic vascular disease, can be above chronobiologic as well as World Health Organization limits for 5 days or longer and can be satisfactory for months thereafter, as validated by continued automatic monitoring. The MESOR can be interpreted in light of clock-hour-, gender-, and age-specified reference limits and thus can be more reliably estimated with a systematic account of major sources of variability than by casual time-unspecified spot checks (that conventionally are interpreted by a fixed and, thus, rhythm, gender-, and age-ignoring limit). With spot checks, in a diagnostically critical range of "borderline" blood pressures, an inference can depend on the clock-hour of the measurement, usually providing a diagnosis of normotension in the morning and of hypertension in the afternoon (for the same diurnally active, nocturnally resting patient!). Long-term treatment must not be based upon the possibility of an afternoon vs a morning appointment. Moreover, the conventional approach will necessarily miss cases of CHAT that are not accompanied by MESOR hypertension. (2) Circadian hyper-amplitude-tension indicates a greater risk for stroke than does an increase in the around-the-clock average blood pressure (above 130/80 mm Hg) or old age, whereas (3) CHAT can be asymptomatic, as can MESOR hyptertension. (4) Deficient heart rate variability, the fall below a threshold of the circadian standard deviation of heart rate, an entity in its own right, is also a chronome alteration of heart rate variability (CAHRV). Deficient heart rate variability can be present together with CHAT, doubling the relative risk of morbid events. In each case--either combined with CHAT or as an isolated CAHRV--a DHRV constitutes an independent diagnostic assessment provided as a dividend by current blood pressure monitors that should be kept in future instrumentation designs. CHAT and DHRV can be screened by systematic focus on variability, preferably by the use of automatic instrumentation and analyses, which are both available (affordably) for research in actual practice, in conjunction with the Halberg Chronobiology Center at the University of Minnesota.

Objective: To make measurable improvements in the quality and cost of neonatal intensive care using a multidisciplinary collaborative quality improvement model., Design: Interventional study. Patient demographic and clinical information for infants with birth weight 501 to 1500 g was collected using the Vermont Oxford Network Database for January 1, 1994 to December 31, 1997., Setting: Ten self-selected neonatal intensive care units (NICUs) received the intervention. They formed 2 subgroups (6 NICUs working on infection, 4 NICUs working on chronic lung disease). Sixty-six other NICUs served as a contemporaneous comparison group., Patients: Infants with birth weight 501 to 1500 g born at or admitted within 28 days of birth between 1994 and 1997 to the 6 study NICUs in the infection group (n = 3063) and the 66 comparison NICUs (n = 21 509); infants with birth weight 501 to 1000 g at the 4 study NICUs in the chronic lung disease group (n = 738)., Interventions: NICUs formed multidisciplinary teams that worked together under the direction of a trained facilitator over a 3-year period beginning in January 1995. They received instruction in quality improvement, reviewed performance data, identified common improvement goals, and implemented "potentially better practices" developed through analysis of the processes of care, literature review, and site visits., Main Outcome Measures: The rates of infection after the third day of life with coagulase-negative staphylococcal or other bacterial pathogens for infants with birth weight 501 to 1500 g, and the rates of oxygen supplementation or death at 36 weeks' adjusted gestational age for infants with birth weight 501 to 1000 g., Results: Between 1994 and 1996, the rate of infection with coagulase-negative staphylococcus decreased from 22.0% to 16.6% at the 6 project NICUs in the infection group; the rate of supplemental oxygen at 36 weeks' adjusted gestational age decreased from 43.5% to 31.5% at the 4 NICUs in the chronic lung disease group. There was heterogeneity in the effects among the NICUs in both project groups. The changes observed at the project NICUs for these outcomes were significantly larger than those observed at the 66 comparison NICUs over the 4-year period from 1994 to 1997., Conclusion: We conclude that multidisciplinary collaborative quality improvement has the potential to improve the outcomes of neonatal intensive care.

Unlabelled: Surfactant therapy has become an effective standard therapy for infants with respiratory distress syndrome (RDS). The first dose may be given either as prophylaxis immediately after delivery, or as rescue after an infant has developed RDS. Second and subsequent doses are currently recommended by the manufacturers to be administered at minimal levels of respiratory support., Purpose: This study compared the relative efficacy of administering second and subsequent doses of Infasurf surfactant at a low threshold (FIO(2) >30%, still requiring endotracheal intubation) versus a high threshold (FIO(2) >40%, mean airway pressure >7 cm H(2)O) of respiratory support., Methods: A total of 2484 neonates received a first dose of surfactant; 1267 reached conventional retreatment criteria and were randomized to be retreated according to low- or high-threshold criteria. They were then retreated at a minimum of 6-hour intervals each time they reached their assigned threshold until receiving a maximum of 4 total doses. Subjects were stratified by whether they received their first dose by prophylaxis or rescue and by whether their lung disease was considered complicated (evidence of perinatal compromise or sepsis) or uncomplicated., Results: Among the patients randomized, 33% of prophylaxis and 23% of rescue subjects met criteria for the complicated stratum. Although infants allocated to the high-threshold strategy were receiving slightly more oxygen at 72 hours, there was no difference in the number receiving mechanical ventilation at 72 hours or in the secondary respiratory outcomes (requirement for supplemental oxygen or mechanical ventilation at 28 days, supplemental oxygen at 36 weeks' postconceptional age, inspired oxygen concentration >60% at any time). However, there was a significantly higher mortality for infants with complicated RDS who had received retreatment according to the high-threshold strategy., Conclusions: We conclude that equal efficacy can be realized by delaying surfactant retreatment of infants with uncomplicated RDS until they have reached a higher level of respiratory support than is the current standard. We speculate that this would result in a substantial cost-saving from less utilization of drug. Conversely, we believe that infants with complicated RDS should continue to be treated by the low-threshold retreatment strategy, which is currently recommended by the manufacturers of the commercially available surfactants.

A joining of chronobiology and endocrinology was achieved in 1974 at a symposium focusing on the critical role of the hypothalamic-pituitary-adrenal network on the basic side and on the first drug to carry timing in its name. The next step is a section on chronobiology in this neuroendocrinology journal. An account of the problems encountered before both asepsis and universal literacy became the law of the profession and of the land serves here as background to endeavors in behalf of chronobiologic literacy. A step toward the latter goal is the use of systematically collected measurements of heart rate and blood pressure evaluated by computer against reference standards from peers of corresponding age, gender and ethnicity. Thereby, an illustrative, clinically relevant aspect of everyday physiology is resolved within the otherwise neglected normal range, and disease risk syndromes are detected so that preventive treatment can be instituted before catastrophic disease occurs. The scope of this chronobiology section of the Neuroendocrinology Letters is to map the time-qualified feedsideward interactions within the neuroendocrines, in the rest of an organism and in the environment. Thereby, we replace time-unqualified feedbacks and feedforwards, along imaginary axes, by neuroendocrine and cellular networks operating predictably insofar as rhythmically within the range of everyday physiology. Subtle effects are thus found that are otherwise covered by the curtain of ignorance drawn over the normal range. More important, feedsidewards account for opposite effects that recur rhythmically, and thus help clarify mechanisms that may underlie the difference between stimulating or inhibiting a malignancy and thus shortening or lengthening the lifespan.

A branched-DNA (bDNA) signal amplification method was used to detect the mecA gene directly from blood culture broth growing staphylococci. BACTEC blood culture bottles with positive growth indices and containing staphylococcus-like organisms as shown by Gram stain were tested for the presence of the mecA gene. Comparison of test results was done among 225 patients (one blood culture from each patient). Compared with PCR, the sensitivity and specificity of the bDNA method are 100 and 99%, respectively. The bDNA test is carried out in a 96-well format and requires approximately 6 h to perform. Our preliminary results suggest that direct detection of the mecA gene by bDNA signal amplification is (i) sensitive enough to detect mecA directly from blood culture bottles without the requirement for subculture and (ii) as sensitive and specific as the PCR-based method.

Week-long or longer monitoring of blood pressure and heart rate, coupled to time-structure analyses, can help detect disease-risk elevations, as a warning of the need for a preventive prehabilitation. Within the normal range of physiologic variation, computer methods quantify time structures, or chronomes, that can serve as reference values. The major applied purpose for mapping chronomes is the detection of disease-risk syndromes such as blood pressure "overswinging" and heart rate "underswinging." Too much blood pressure variability (circadian hyperamplitude tension; CHAT), is a risk factor for vascular disease. Other risk syndromes are chronome alterations of heart rate variability (CAHRVs), consisting of a loss of "jitter", i.e., a reduced standard deviation of heart rate or of alterations in the spectral element of the heart-rate-variability chronome, such as in the correlation dimension, an endpoint of deterministic chaos. These alterations can again serve for prehabilitation. On the basic side, the spectral element of the heart-rate-variability chronomes extends from focus on the heartbeat's period of about 1 second to periods in heart rate and its standard deviation that are numerical equivalents of about 10.5- and about 21-year cycles of solar activity. A seemingly unnatural physiologic rhythm or pattern (such as one of 81.6 hours) may correspond numerically to a purely physical environmental rhythm. For example, interplanetary magnetic storms, with their cycles as external chronome components, trigger myocardial infarctions, strokes, and traffic accidents. The systematic monitoring of external rhythms along with physiologic ones for the concurrent analysis of rhythms with longer and longer periods could detect alterations anywhere in and between the 1 cycle/sec and the 1 cycle/10.5- or 21-years regions of the spectrum. Chronobiomimetic engineering for discovering both instantaneous and long-term chronorisk alterations can provide warnings of increased risk. If risk-lowering therapy is then instituted automatically, instrumented health care will be extended beyond the pacemaker-cardioverter-defibrillator, which focuses on the frequency of 1 cycle/sec. Instrumentation that automatically detects blood pressure that varies too much and heart rate that varies too little is needed for prompting prophylactic CHAT and CAHRV treatment. A database of reference values that can be used for chronodiagnosis is now accumulating.

Evidence here cited underlies resolutions at international meetings to initiate a chronobiology project for health improvement. This project demonstrates expeditiously the feasibility and the health benefits of incorporating chronomedical considerations in the diagnosis, treatment, and prevention of one (or a few closely related) vascular (and oncological) diseases, that have high awareness and importance in the public perspective. Thereby, chronomedicine should become a mainstream basic and applied speciality leading to continual improvement in national/international health status. Reference data obtained for health care can also serve to give a better understanding of the relationship between the terrestrial biosphere and cosmoi near and far.

Objective: To compare the effectiveness of a prophylactic surfactant treatment strategy (PRO) to the effectiveness of a rescue (RESC) surfactant treatment strategy in patients at high risk for developing hyaline membrane disease (HMD)., Study Design: We analyzed data from a retrospective cohort consisting of all patients admitted to the neonatal intensive care units at the centers participating in the recently completed Infasurf-Survanta Comparative Trial. To be in the cohort, a patient had to be admitted during the trial, be <48 hours of age on admission, have a gestational age of <30 weeks, have a birth weight of 501 to 1250 gm, and be free of congenital anomalies. Twelve centers participated in this study. They contributed 1097 patients of whom 381 were treated with a PRO strategy., Results: Survival was significantly higher in the PRO-strategy patients (84% vs 72%, p < 0.05) as was survival without oxygen requirement at a postconceptional age of 36 weeks (60% vs 46%, p < 0.05). In addition, the patients with PRO had a lower prevalence of grade III and IV intraventricular hemorrhage (IVH, 9% vs 14%, p < 0.05). All analyses were controlled for birth weight and type of study center., Conclusion: These data support the conclusion that using a PRO treatment strategy results in improved survival in patients at risk for developing HMD. A PRO treatment strategy may also decrease the likelihood of developing a severe IVH.

The identification of methicillin-resistant staphylococcus isolates in the clinical laboratory has typically been performed by using methods that detect phenotypic expression of resistance determinants. However, these methods may be difficult to interpret and some isolates do not express resistance until selective pressure is administered. Assays that detect genetic determinants are not subject to these limitations and have been effective in distinguishing isolates that are capable of expressing the resistance phenotype. In this study, a novel branched-DNA (bDNA) hybridization assay was used to test for the mecA gene in 416 clinical staphylococcal isolates. The results were compared with those obtained by a PCR-based assay and oxacillin disk diffusion. For 155 Staphylococcus aureus and 261 coagulase-negative Staphylococcus isolates, the bDNA assay and PCR results were 100% concordant. Among the S. aureus isolates, 20 were MecA+ and 135 were MecA-. For the coagulase-negative staphylococci, 150 were MecA+ and 111 were MecA-. The results from the genotypic detection methods were compared with those obtained by oxacillin disk diffusion. No discrepancies were detected among the S. aureus isolates; however, 10 coagulase-negative isolates were MecA+ but oxacillin sensitive and 1 isolate was MecA- but oxacillin resistant. Oxacillin resistance was induced in 6 of the 10 MecA+ isolates previously classified as oxacillin sensitive. These results suggest that the bDNA method described here is a sensitive and efficient method for detection of methicillin resistance in staphylococci and that genetic detection methods may be useful for detection of potential methicillin resistance in the clinical laboratory.

Previously published average curves of heart rate and duration of ischemia in patients with coronary artery disease, studied while on placebo or on treatment with either atenolol or diltiazem, are re-analysed for the assessment of about-daily (circadian) and about-weekly (circaseptan) changes in these variables and of any treatment effect on rhythm characteristics. In addition to circadians, a circaseptan pattern characterizes the duration of ischemia in all three aforementioned study stages. Both drugs decrease the duration of ischemia, atenolol, but not diltiazem, also affects the circadian amplitude and acrophase of this variable. A circaseptan pattern is also found for heart rate on placebo and on treatment with atenolol, but not with diltiazem. Both drugs lower heart rate and the circadian amplitude and 24-h standard deviation of heart rate, atenolol much more markedly than diltiazem. Circadian and circaseptan rhythm characteristics and their alterations with treatment serve to optimize treatment by timing its administration. Chronobiologic surveillance of variables that are being readily monitored as-one-goes by modern implantable devices can also serve for the validation of the effectiveness of drug and electrical therapy. Rhythm alterations, in turn, can provide the earliest warnings of an elevated disease risk and lead to an improved diagnosis.

Objective: To compare the relative safety and efficacy of Infasurf (calf lung surfactant extract; ONY, Inc, Amherst, NY, IND #27169) versus Survanta (Beractant, Ross Laboratories, Columbus, OH) in reducing the acute severity of respiratory distress syndrome (RDS) when given at birth and to infants with established RDS., Design: A prospective, randomized, double-blind, multicenter clinical trial., Setting: Thirteen neonatal intensive care units participated in the treatment arm: seven of these concurrently participated in the prevention arm., Patients: The treatment arm enrolled infants of

Objective: Although numerous trials have demonstrated the efficacy of exogenous surfactant for prophylaxis or treatment of neonatal respiratory distress syndrome (RDS), optimum timing of administration remains controversial. One previous study showed that administration of calf lung surfactant extract immediately following birth, to neonates born before 30 weeks postconceptional age, was preferable to delaying administration until after development of RDS. The current study was designed to test a similar hypothesis for babies born between 29 and 32 weeks gestational age., Design: One thousand three hundred ninety-eight neonates with obstetric estimates of 29 through 32 weeks' gestation were randomized to receive CLSE at birth or to wait until development of mild RDS. After exclusions for malformations and other factors, data from 1248 were analyzed., Results: Prophylaxis was associated with less development of moderate RDS (7% vs 12%), less need for retreatment (5% vs 9%), less need for mechanical ventilation or supplemental oxygen during the first 4 days, and fewer deaths or less requirement for supplemental oxygen at 28 days (5% vs 9%). Although 1-minute Apgar scores were significantly lower in the prophylaxis group, the difference disappeared by the 5-minute score and there was no difference in the incidence of asphyxia-related complications. Sixty percent of the neonates assigned to early treatment received endotracheal intubation and 43% received calf lung surfactant extract at a median age of 1.5 hours. When data were analyzed by gestational age and birth weight subgroups, most of the differences could be attributable to babies born at 30 weeks or less or weighing less than 1500 g, probably because of the higher incidence of surfactant deficiency in this more immature subgroup.

An 1180-g infant with esophageal atresia and tracheoesophageal fistula developed life-threatening respiratory distress syndrome. Conventional mechanical ventilation resulted in gastric perforation and pneumoperitoneum. High-frequency ventilation stabilized the infant, permitting distal occlusion of the esophagus with a Silastic band. Fistula ligation was subsequently performed under more optimal physiologic conditions.

On the occasion of Franz Halberg's 70th birthday, some of his many achievements are reviewed. We provide a historical background to the development of chronobiology; offer insight into the current state of this new science; and sketch the promise of this discipline for health care and cure. As a tribute to Franz Halberg, in an era of fast-growing technology, an attempt is made to describe his perspective of tomorrow's medicine and biology. The many students he trained throughout his productive career face the challenge of deserving the trust he placed in them and of further implementing his vision. A leader in social pediatrics put it aptly: it will take several generations of researchers to study and master his life's work.

Preterm triplets were treated with calf lung surfactant extract (CLSE). Two were treated at birth without development of respiratory distress syndrome (RDS); one was treated after development of RDS, with rapid improvement. These cases demonstrated the efficacy of exogenous surfactant and the potential benefit of prophylaxis (early treatment) over late treatment. Although various exogenous surfactants have been used successfully to treat or prevent RDS in preterm infants, the optimal time of surfactant treatment has not been established. Surfactant therapy at birth results in a reduction in the incidence and severity of RDS, but it could lead to unnecessary treatment in a significant portion of patients. On the other hand, delaying treatment is likely to lessen the benefits of exogenous surfactant by various factors, including barotrauma and oxygen toxicity. The triplets in this report were treated with Infasurf CLSE. Two were treated at birth without development of RDS, but one was treated after development of RDS, with rapid improvement of respiratory status.