Paula Delmore

Technique for Intrapartum Administration of Surfactant without Requirement for an Endotracheal Tube

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 cmH2O was administered by mask as the babies initiated breathing. Nasal CPAP at 6 cmH2O 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.

Reducing Acquired Infections in the NICU: Observing and Implementing Meaningful Differences in Process Between High and Low Acquired Infection Rate Centers

BACKGROUND: Acquired infection is one of the most prevalent sources of concern in neonatal intensive care units (NICUs). Center-to-center variation has been noted by both the National Nosocomial Infection Surveillance System and the Vermont Oxford Network suggesting that site of care influences outcomes including acquired infection.OBJECTIVE: To reduce the acquired infection rate by isolating and then implementing meaningful process differences between high and low infection rate centers.DESIGN/METHOD: A multistaged observation and intervention study. The primary outcome measure was defined as a positive blood culture, collected more than 3 days after birth. Hospital patient days along with infection episodes were collected for all NICU admissions in the network during the baseline and postimplementation periods. A detailed observation guide was used during site visits to high and low infection rate centers. The observations recorded in the guide allowed the team to isolate meaningful differences, which were shared with the network. Individual NICUs decided which of the meaningful differences, if any, to implement. To estimate the impact on costs, additional data were gathered in a case-matched series of infants in one demonstration site.RESULTS: In all, 15 meaningful differences were isolated and shared with the network. The network rate for acquired infection dropped from 3.8 to 2.9 episodes per 1000 patient days. In the demonstration site, the infection rate dropped from 7.4 to 4.0 per 1000 patient days.CONCLUSION: Isolation of process level differences between high and low performing centers followed by implementation of these meaningful differences may reduce acquired infections. Other targeted areas of care may benefit from this quality improvement methodology.

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 × (PMA3.1/(43.63.1 + PMA3.1)); V (l) = 61.8 × (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings support age‐based dosing.

Characterization of the Population Pharmacokinetics of Ampicillin in Neonates Using an Opportunistic Study Design

ABSTRACT 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.

Respiratory distress syndrome and tracheoesophageal fistula: Management with high-frequency ventilation

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. (Grit Care Med 1990; 18:447)

Simultaneous determination of trimethoprim and sulfamethoxazole in dried plasma and urine spots.

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.

Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

ABSTRACT 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.)

The absolute nucleated red blood cell (aNRBC) count at birth is not an indicator for retinopathy of prematurity (ROP)

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. Wilcoxons 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.

Population Pharmacokinetics of Intramuscular and Intravenous Ketamine in Children

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.

An anthropometric survey of US pre-term and full-term neonates

Abstract 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.