Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.

Pharmacokinetic models rarely undergo external validation in vulnerable populations such as critically ill infants, thereby limiting the accuracy, efficacy, and safety of model-informed dosing in real-world settings. Here, we describe an opportunistic approach using dried blood spots (DBS) to evaluate a population pharmacokinetic model of metronidazole in critically ill preterm infants of gestational age (GA) ≤31 weeks from the Metronidazole Pharmacokinetics in Premature Infants (PTN_METRO, NCT01222585) study. First, we used linear correlation to compare 42 paired DBS and plasma metronidazole concentrations from 21 preterm infants [mean (SD): post natal age 28.0 (21.7) days, GA 26.3 (2.4) weeks]. Using the resulting predictive equation, we estimated plasma metronidazole concentrations (ePlasma) from 399 DBS collected from 122 preterm and term infants [mean (SD): post natal age 16.7 (15.8) days, GA 31.4 (5.1) weeks] from the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP, NCT01994993) trial. When evaluating the PTN_METRO model using ePlasma from the SCAMP trial, we found that the model generally predicted ePlasma well in preterm infants with GA ≤31 weeks. When including ePlasma from term and preterm infants with GA >31 weeks, the model was optimized using a sigmoidal Emax maturation function of postmenstrual age on clearance and estimated the exponent of weight on volume of distribution. The optimized model supports existing dosing guidelines and adds new data to support a 6-hour dosing interval for infants with postmenstrual age >40 weeks. Using an opportunistic DBS to externally validate and optimize a metronidazole population pharmacokinetic model was feasible and useful in this vulnerable population.

Randomised trial estimating length of endotracheal tube insertion using gestational age or nasal-tragus length in newborns: a study protocol.

INTRODUCTION: Endotracheal tube (ETT) insertion depth estimation is important for optimal placement of ETT tip and balanced ventilation of the lungs. Various methods are available to determine the ETT insertion depth. The Neonatal Resuscitation Programme recommends the gestational age and nasal-tragus length (NTL) methods for estimating ETT insertion depth during cardiopulmonary resuscitation. However, the prospective data comparing these two methods is lacking. METHODS AND ANALYSIS: This is an open-label multi-centre randomised controlled trial, where gestational age and NTL methods will be used to determine the initial ETT insertion depth in term and preterm infants that are less than 28 days old, requiring oral intubation in the delivery room or neonatal intensive care unit (NICU). SITES AND SAMPLE SIZE: The trial is aimed to recruit 454 infants over 3 years across tertiary level NICUs. OUTCOMES: The primary outcome includes an optimally positioned ETT, defined as an ETT tip between the upper border of the first thoracic vertebra and the lower border of the second thoracic vertebra. The outcome is assessed by a paediatric radiologist, who will be masked to the group assignment. Secondary outcomes are malpositioned ETT tips, pneumothorax, ETT repositioning, chronic lung disease, invasive ventilation days, and death. ANALYSIS: Data will be analysed using the intention-to-treat principle. The primary and categorical secondary outcomes will be compared using the χ2 test. Adjusted risk ratios of outcomes will be calculated along with 95% CIs through multivariable logistic regression analysis, including covariates deemed biologically to influence the outcomes. ETHICS AND DISSEMINATION: The study has been approved by the PNU Research Ethics Board (20-0148) and the respective ethical review boards of the participating centres. The results will be disseminated through conference meetings, social media platforms, and publications in scientific journals. TRIAL REGISTRATION NUMBER: NCT04393337.

Antibiotic Safety and Effectiveness in Premature Infants With Complicated Intraabdominal Infections.

BACKGROUND: In premature infants, complicated intraabdominal infections (cIAIs) are a leading cause of morbidity and mortality. Although universally prescribed, the safety and effectiveness of commonly used antibiotic regimens have not been established in this population. METHODS: Infants ≤33 weeks gestational age and <121 days postnatal age with cIAI were randomized to ≤10 days of ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam and gentamicin (group 3) at doses stratified by postmenstrual age. Due to slow enrollment, a protocol amendment allowed eligible infants already receiving study regimens to enroll without randomization. The primary outcome was mortality within 30 days of study drug completion. Secondary outcomes included adverse events, outcomes of special interest, and therapeutic success (absence of death, negative cultures, and clinical cure score >4) 30 days after study drug completion. RESULTS: One hundred eighty infants [128 randomized (R), 52 nonrandomized (NR)] were enrolled: 63 in group 1 (45 R, 18 NR), 47 in group 2 (41 R, 6 NR), and 70 in group 3 (42 R, 28 NR). Thirty-day mortality was 8%, 7%, and 9% in groups 1, 2, and 3, respectively. There were no differences in safety outcomes between antibiotic regimens. After adjusting for treatment group and gestational age, mortality rates through end of follow-up were 4.22 [95% confidence interval (CI): 1.39-12.13], 4.53 (95% CI: 1.21-15.50), and 4.07 (95% CI: 1.22-12.70) for groups 1, 2, and 3, respectively. CONCLUSIONS: Each of the antibiotic regimens are safe in premature infants with cIAI. CLINICAL TRIAL REGISTRATION: NCT0199499.

Safety of Metronidazole in Late Pre-term and Term Infants with Complicated Intra-abdominal Infections.

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.

Oral dextrose reduced procedural pain without altering cellular ATP metabolism in preterm neonates: a prospective randomized trial.

OBJECTIVE: To examine the effects of 30% oral dextrose on biochemical markers of pain, adenosine triphosphate (ATP) degradation, and oxidative stress in preterm neonates experiencing a clinically required heel lance. STUDY DESIGN: Utilizing a prospective study design, preterm neonates that met study criteria (n = 169) were randomized to receive either (1) 30% oral dextrose, (2) facilitated tucking, or (3) 30% oral dextrose and facilitated tucking 2 min before heel lance. Plasma markers of ATP degradation (hypoxanthine, uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured using the premature infant pain profile-revised (PIPP-R). RESULTS: Oral dextrose, administered alone or with facilitated tucking, did not alter plasma markers of ATP utilization and oxidative stress. CONCLUSION: A single dose of 30% oral dextrose, given before a clinically required heel lance, decreased signs of pain without increasing ATP utilization and oxidative stress in premature neonates.

Fostering self-awareness in collaborative reflective training: Commentary response.

Replies to comments by DeCaporale-Ryan, Dadiz, and Peyre (see record 2016-27364-002) on the original article by Kim, Hernandez, Lavery, and Denmark (see record 2016-18380-001). The current authors thank DeCaporale-Ryan, Dadiz, and Peyre for presenting a rich theoretical counterpoint to their article and respond to issues they raised regarding their collaborative reflecting team (CRT) model.

Stimulating reflective practice using collaborative reflective training in breaking bad news simulations.

Medical simulation has long been used as a way to immerse trainees in realistic practice scenarios to help them consolidate their formal medical knowledge and develop teamwork, communication, and technical skills. Debriefing is regarded as a critical aspect of simulation training. With a skilled debriefing facilitator, trainees are able to go beyond a rote review of the skills and steps taken to explore their internal process and self-reflect on how their experience during the simulation shaped their decision making and behavior. However, the sense of vulnerability is an aspect of experiential training that can raise a trainee's defensiveness. Anxiety increases when trainees anticipate being evaluated for their performance, or when the simulation scenario pertains to complex interpersonal activities such as learning how to break bad news (BBN), a commonly encountered aspect of medical practice with inadequate training. Thus, collaborative reflective training (CRT), developed out of ideas based in family therapy, was designed as an approach for facilitating open dialogue and greater self-reflection while receiving training in BBN. This article will discuss the conceptual framework of CRT, explain how it was developed, and describe the nature of how it was used with a team of neonatology and pediatric fellows and medical family therapy interns. (PsycINFO Database Record

Urinary NGAL in premature infants.

Premature infants are at unique risk for developing acute kidney injury (AKI) due to incomplete nephrogenesis, early exposure to nephrotoxic medications, and coexisting conditions such as patent ductus arteriosus (PDA) and respiratory distress syndrome (RDS). Unfortunately, laboratory testing for the diagnosis of AKI in this population is problematic because of the physiology of both the placenta and the extra-uterine premature kidney. Recent research has led to the development of promising biomarkers for the early detection of AKI in children but there are no published reports in neonates. Our goal was to determine whether urine neutrophil gelatinase-associated lipocalin (NGAL) was detectable in premature infants and to correlate levels with gestational age, birth weight (BW), or indomethacin exposure. We enrolled 20 infants in four BW groups: 500-750, 751-1000, 1001-1250, and 1251-1500 g. Urine was collected every day for the first 14 d of life. Neonates born at earlier gestational ages and lower BWs had higher urine NGAL levels (p < 0.01). We conclude that urine NGAL is easily obtained in premature infants and that it correlates significantly with both BW and gestational age. The use of urinary NGAL as a biomarker of AKI in premature infants warrants further investigation.