Faculty Bibliography

INTRODUCTION/BACKGROUND:Meropenem-vaborbactam is a new β-lactam/β-lactamase inhibitor combination designed to target Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae. Meropenem-vaborbactam was Food and Drug Administration FDA approved for complicated urinary tract infections (cUTI) in patients 18 years of age or older. An understanding of the pharmacokinetics of meropenem when given in combination with vaborbactam is important to understanding the dosing of meropenem-vaborbactam. Additionally, the safety and efficacy of meropenem-vaborbactam in a pediatric patient has yet to be described in the literature. METHODS:Retrospective single patient chart review. RESULTS:A 4-year-old male with short bowel syndrome, colostomy and gastro-jejunal tube, bronchopulmonary dysplasia, and a central line for chronic total parenteral nutrition (TPN) and hydration management, complicated with multiple central line-associated bloodstream infections (BSI), was brought to our medical center with fever concerning for a BSI. On day 2 the patient was started on meropenem-vaborbactam at a dose of 40 mg/kg/dose every 6 hours infused over 3 hours for KPC-producing K. pneumoniae BSI. Meropenem serum concentrations obtained on day 5 of meropenem-vaborbactam therapy, immediately following the completion of the infusion and 1 hour after the infusion, were 51.3 and 13.6 μg/ml, respectively. Serum concentrations correlated to a volume of distribution of 0.59 L/kg and a clearance (CL) of 13.1 ml/min/kg. Repeat blood cultures remained negative, and meropenem-vaborbactam was continued for a total of 14 days CONCLUSION: A meropenem-vaborbactam regimen of 40 mg/kg/dose every 6 hours given over 3 hours was successful in providing a target attainment of 100% for meropenem serum concentrations above the minimum inhibitory concentration MIC for at least 40% of the dosing interval and was associated with successful bacteremia clearance in a pediatric patient.

BACKGROUND:oxygenator. METHODS:Quarter-inch and 3/8-inch, simulated, closed-loop, ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. A one-time dose of DAP was administered into the circuit and serial pre- and post-oxygenator concentrations were obtained at 0-5 minutes and 1, 2, 3, 4, 5, 6 and 24-hour time points. DAP was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation Results: For both the 1/4-inch and 3/8-inch circuits, there was no significant DAP loss at 24 hours. Additionally, the reference DAP concentrations remained relatively constant during the entire 24-hour study period. CONCLUSION/CONCLUSIONS:This ex-vivo investigation demonstrated no significant DAP loss within an ECMO circuit with both sizes of the Quadrox-i oxygenator at 24 hours. Therapeutic concentrations of DAP in the setting of ECMO may be anticipated with current recommended doses, depending on the amount of extracorporeal volume needed for circuit maintenance in comparison to the patient's apparent volume of distribution. Additional studies with a larger sample size are needed to confirm these findings.

OBJECTIVES/OBJECTIVE:To determine the oxygenator impact on alterations of ceftaroline in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation circuit including the Quadrox-i oxygenator (Maquet, Wayne, NJ). DESIGN/METHODS:Quarter-inch and 3/8-inch, simulated closed-loop extracorporeal membrane oxygenation circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. An one-time dose of ceftaroline was administered into the circuits, and serial pre- and postoxygenator concentrations were obtained at 5 minutes, 1-, 2-, 3-, 4-, 5-, 6-, and 24-hour time points. Ceftaroline was also maintained in a glass vial, and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. SETTING/METHODS:A free-standing extracorporeal membrane oxygenation circuit. PATIENTS/METHODS:None. INTERVENTION/METHODS:Single dose administration of ceftaroline into closed-loop extracorporeal membrane oxygenation circuits prepared with and without an oxygenator in series with serial preoxygenator, postoxygenator, and reference samples obtained for concentration determination over a 24-hour study period. MEASUREMENTS AND MAIN RESULTS/RESULTS:For the 1/4-inch circuit with an oxygenator, there was 79.8% drug loss preoxygenator and 82.5% drug loss postoxygenator at 24 hours. There was a statistically significant difference (p < 0.01) in the amount of ceftaroline remaining at 24 hours when compared with each prior time point for the 1/4-inch circuit. For the 1/4-inch circuit without an oxygenator, there was no significant drug loss at any study time point. For the 3/8-inch circuit with an oxygenator, there was 76.2% drug loss preoxygenator and 77.6% drug loss postoxygenator at 24 hours. There was a statistically significant difference (p < 0.01) in the amount of ceftaroline remaining at 24 hours when compared with each prior time point for the 3/8-inch circuit. For the 3/8-inch circuit without an oxygenator, there was no significant drug loss at any study time point. The reference ceftaroline concentrations remained relatively constant during the entire study period demonstrating the ceftaroline loss in each size of the extracorporeal membrane oxygenation circuit with or without an oxygenator was not a result of spontaneous drug degradation and primarily the result of the oxygenator. CONCLUSIONS:This ex vivo investigation demonstrated significant ceftaroline loss within an extracorporeal membrane oxygenation circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours. Therapeutic concentrations of ceftaroline in the setting of extracorporeal membrane oxygenation may not be achieved with current U.S. Food and Drug Administration-recommended doses, and further evaluation is needed before specific drug dosing recommendations can be made for clinical application with extracorporeal membrane oxygenation.

Introduction/Aim: NYU Langone Health's first neonatal ECMO patient was in March 2015, marking the start of the Pediatric and Neonatal ECMO Program within the institution. Since then, our program averages 5 ECMO patients per fiscal year (September 1 to August 31). A core ECMO Team, consisting of a Medical Director, a Surgical Director, an ECMO coordinator, 2 Chiefs of Perfusion, and 3 ECMO Intensivists, was identified to establish a reservoir of ECMO expertise within our new, low volume ECMO program. When a patient requires ECMO support, the core ECMO Team collaborates with the multidisciplinary ICU team to optimize both patient and circuit management. The teams provide concurrent care with the ECMO Team overseeing all ECMO-related decision making. Despite having the core ECMO Team as a resource during each ECMO case, a low volume of ECMO patients per year augments slower institutional learning and highlights the need for more frequent educational opportunities. The core ECMO Team worked together to create a recurring multidisciplinary Pediatric ECMO In-situ Simulation to bridge the educational gap in a new, low volume ECMO center. Material and Methods: The goal of establishing Pediatric ECMO In-Situ Simulation was to have either a real life patient on ECMO support or have a simulated ECMO patient once a month to establish routine ECMO exposure and promote multidisciplinary learning and competency. The first simulation session took place in September 2017. For 9 consecutive months, we achieved this goal with 4 real life ECMO patients and 5 simulated ECMO patients. Each simulation session took place over 4 hours and included a complete critical care team, consisting of an ICU Attending Physician, an Advanced Practice Provider, a Resident, 2 Critical Care Nurses, a Perfusionist, and a Respiratory Therapist. Pre-and postsimulation, participants completed self-assessments and knowledge tests, which were then, analyzed using the Wilcoxon Signed-rank test. Simulation logistics included a high fidelity simulation mannequin that was connected to a running ECMO circuit, as well as IV infusions and a mechanical ventilator. Simulation medications, fluids, blood products, and bedside supplies were readily available for the participants. Contact information to simulated ancillary departments, such as Inpatient STAT Lab, Blood Bank and Radiology, was distributed. We also collaborated with Hospital Informatics to create a virtual medical record for the simulated patient, which allowed the participants to view the ECMO order set, lab values, imaging results, vital signs, etc. The participants could also place orders in real time and document in the "patient's" medical record. The primary learning objective of the simulation was to improve competency in the daily management of an ECMO patient with less emphasis on ECMO circuit troubleshooting and emergency management. Scenarios included routine ECMO practices, such as conducting multidisciplinary ECMO rounds, adhering to programmatic processes, completing hourly patient assessments and documentation requirements, and monitoring patient fluid volume status. Results: 27 participants took pre-and post-course tests to assess their ECMO knowledge. They also filled out pre-and post-course selfassessments to determine their level of self-confidence in caring for an ECMO patient. One participant was excluded from the data analysis due to incomplete test scores and survey responses. Using the Wilcoxon Signed-rank test, we found a statistically significant improvement in the self-assessment scores (p=0.00001284). There was also a trend towards improvement in the knowledge scores (p=0.09). Conclusions: High fidelity in-situ simulation targeting various learner groups is effective with improvement in self-confidence and written knowledge. Recurring simulation opportunities in a new, low volume ECMO Center promotes continued familiarity and experience in caring for ECMO patients. Next steps include conducting multiple simulation sessions throughout a longer time span, such as over a 12 to 24 hour period

Introduction/Aim: Our Pediatric ECMO Program was launched in March of 2015. Based on historical volumes and projections we anticipated a low volume center. Per ELSO Guidelines, ECMO centers require institutional structure and organization for effective use of ECMO therapy. Also, literature review of pediatric ECMO patient outcomes imply that high volume ECMO centers are associated with improved survival rates in pediatric ECMO patients. Our goal was to implement a formal Pediatric ECMO Program, along with a structured educational course, to demonstrate that successful patient survival rates are obtainable in a low volume ECMO center. Material and Methods: A comprehensive review was completed to identify gaps and areas for improvement within the current state of ECMO at the institution with the goal of establishing an ECMO Program, per ELSO Guidelines, that ensures safe use of ECMO, improved patient outcomes, and optimized programmatic processes. Interventions implemented to formalize the ECMO Program included establishment of clinical practice guidelines and protocols, creation of an ECMO credentialing process, standardization of intrahospital processes related to ECMO, and organization of patient data collection. To assure reasonable use of this resource all cannulation and decannulation decisions required agreement of both the Medical and Surgical ECMO Directors. Formalization of the interprofessional collaboration with the critical care teams and ancillary departments was established with structured morning and evening rounds. Collaboration continued through implementation of formal multidisciplinary team meetings, including patient case reviews and quality assurance meetings. Last, a primary intervention in formalization of an ECMO Program was the establishment of an ECMO education course that was required for all providers who would be involved in the care of ECMO patients. The course was geared towards frontline critical care physicians and advanced practice providers caring for pediatric ECMO patients. The course included didactic learning and simulation training with a high fidelity simulation mannequin and a running ECMO circuit. Pre-and postcourse, participants completed self-assessments and knowledge tests. Results: Since March 2015, our Pediatric ECMO Program averages 5 ECMO patients per fiscal year (September 1 to August 31). In the first fiscal year (FY) 2015, our survival from ECMO rate was 33% with 0% of our patients surviving to discharge. Our hemorrhagic and neurologic complication rates were 67%. The formalization of our ECMO Program and implementation of ECMO education occurred in April 2016, mid FY 2016. Our survival from ECMO rate for FY 2016 improved from 33% to 86%, showing a 160.6% increase. Subsequently, our survival from ECMO rates continued to improve with FY 2017 having 100% survival rate and FY 2018 having 80% survival rate. We also observed a notable decrease in hemorrhagic and neurologic complications per FY. These complications decreased by 40.3% and 70.1%, respectively. Along with tracking our ECMO patient outcomes and complications, our program closely monitors our ECMO consults. Since March 2015, we average 23 ECMO consults per FY with an average of 5 patients (20%) placed on ECMO and 18 patients (80%) denied from ECMO. Out of the patients who were denied ECMO support, 30% of patients expired and 70% of patients recovered and survived to discharge, emphasizing the importance of strict patient selection criteria and centralized ECMO decision-making. For our ECMO course results, our team has held seven courses since August 2016. Among the first time participants (n=82), 84% showed improvement, 10% did worse, and 6% had incomplete data in their post-test written knowledge test. Conclusions: Despite a low institutional case volume of ECMO patients, creation of a structured ECMO Program with a recurring comprehensive ECMO course, promotes both self-confidence and clinical abilities of the multidisciplinary critical care team, as well as improves patient outcomes. Ongoing data collection and quality improvement will be essential to maintain this high level of performance

BACKGROUND:Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. METHODS:We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS:Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. CONCLUSIONS:Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

OBJECTIVES/OBJECTIVE:There is a lack of standardization and supporting data regarding the duration preassembled and preprimed extracorporeal membrane oxygenation (ECMO) circuits are expected to be sterile. Therefore, the purpose of this study was to prospectively evaluate whether preassembled and preprimed ECMO circuits could maintain sterility for a period up to 65 days. DESIGN/METHODS:Four ECMO circuits (2 neonatal/pediatric¼" and 2 adolescent/adult ⅜ ") were assembled and primed under sterile conditions and maintained at room temperature. Culture samples were obtained from each circuit and plated within 1 hour. Culture samples were obtained on day 0 when assembled and primed then every 5 days up to day 65. Samples were plated on several different media including the following: blood agar plate: trypticase soy agar with 5% sheep blood, MacConkey agar, and thioglycollate broth then incubated at 35°C for 3 days. RESULTS:All cultures obtained from the priming solution from of the¼" and ⅜ " ECMO circuits produced no microbial or fungal growth for the 65-day study period. CONCLUSION/CONCLUSIONS:These pilot data suggest preprimed ECMO circuits may maintain sterility for a period up to 65 days. Additional studies evaluating a larger number of ECMO circuits are needed to confirm these findings.

OBJECTIVES/OBJECTIVE:To describe the ceftaroline pharmacokinetics in critically ill children treated for suspected or confirmed methicillin-resistant Staphylococcus aureus infections, including blood stream infection and describe the microbiological and clinical outcomes. DESIGN/METHODS:Retrospective electronic medical record review. SETTINGS/METHODS:Free-standing tertiary/quaternary pediatric children's hospital. PATIENTS/METHODS:Critically ill children receiving ceftaroline monotherapy or combination therapy for suspected or confirmed methicillin-resistant S. aureus infections in the PICU. INTERVENTION/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Seven patients, three females (43%), and four males (57%), accounted for 33 ceftaroline samples for therapeutic drug management. A median of four samples for therapeutic drug management was collected per patient (range, 2-9 samples). The median age was 7 years (range, 1-13 yr) with a median weight of 25.5 kg (range, 12.6-40.1 kg). Six of seven patients (86%) demonstrated an increase in volume of distribution, five of seven patients (71%) demonstrated an increase in clearance, and 100% of patients demonstrated a shorter half-life estimate as compared with the package insert estimate. Six of seven patients (85.7%) had documented methicillin-resistant S. aureus growth from a normally sterile site with five of six (83.3%) having documented BSI, allowing six total patients to be evaluated for the secondary objective of microbiological and clinical response. All six patients achieved a positive microbiological and clinical response for a response rate of 100%. CONCLUSIONS:These data suggest the pharmacokinetics of ceftaroline in PICU patients is different than healthy pediatric and adult patients, most notably a faster clearance and larger volume of distribution. A higher mg/kg dose and a more frequent dosing interval for ceftaroline may be needed in PICU patients to provide appropriate pharmacodynamic exposures. Larger pharmacokinetic, pharmacodynamic, and interventional treatment trials in the PICU population are warranted.

OBJECTIVE: There is increasing data in pediatrics demonstrating procalcitonin (PCT) is more sensitive and specific than other biomarkers in the setting of bacterial infections. However, the use of PCT in neonatal and pediatric extracorporeal membrane oxygenation (ECMO) is not well described. Therefore, the purpose of this study was to describe the clinical utility of PCT in determining the absence or presence of bacterial infections in neonatal and pediatric patients on ECMO. METHODS: This was a retrospective electronic medical record (EMR) review of data between January 1, 2010 to June 30, 2016 at a single, free-standing, children 's hospital. All patients on ECMO with >/=1 PCT level obtained while receiving ECMO support were eligible for inclusion. The EMR was searched for chest radiographs (CXR) and bacterial culture results (urine, blood, cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL) and respiratory cultures). All bacterial and viral cultures obtained within 5 days of PCT levels being obtained were analyzed. PCT levels of 0.5, 0.9, 1.0, 1.4 and 2.0 were used as the initial cut-off values for the analysis. The sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV) and likelihood ratios were calculated for each of the PCT levels. RESULTS: Twenty-seven patients met the inclusion criteria and contributed 193 PCT values for the analysis. The median age was 8 months (range 0 days to 18 years). Linear regression analysis demonstrated that a PCT cut-off of 0.5, 0.9 and 1.4 predicted the presence of a bacterial infection. The PCT value with the most utility was 0.5, with a sensitivity of 92%, a specificity of 43%, a positive predictive value of 60% and a negative predictive value (NPV) of 86%. CONCLUSION: This is the largest data set evaluating PCT in neonatal and pediatric patients on ECMO. A PCT value of 0.5 ng/mL had the most utility for determining the absence or presence of a bacterial infection in the setting of ECMO with a high sensitivity and NPV.

OBJECTIVES: To determine whether contemporary beta-lactam anti-infective dosing recommendations in critically ill children achieve concentrations associated with maximal anti-infective activity. The secondary objective was to describe the microbiological and clinical outcomes associated with beta-lactam therapeutic drug management. DESIGN: Electronic Medical Record Review. SETTING: A 189-bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA. PATIENTS: Patients admitted to the PICU from September 1, 2014, to May 31, 2017, with sepsis and those receiving extracorporal therapy with either extracorporeal membrane oxygenation or continuous renal replacement therapy that had routine beta-lactam therapeutic drug management. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-two patients were in the total cohort and 23 patients in the infected cohort accounting for 248 samples for therapeutic drug management analysis. The median age was 1 year (range, 4 d to 18 yr) with a mean weight of 19.7 +/- 22.3 kg (range, 2.7-116 kg). Twenty-three patients (28%) had growth of an identified pathogen from a normally sterile site. Seventy-eight of 82 patients (95%) had subtherapeutic anti-infective concentrations and did not attain the primary pharmacodynamic endpoint. All patients in the infected cohort achieved a microbiological response, and 22 of 23 (95.7%) had a positive clinical response. CONCLUSIONS: Overall, 95% of patients had subtherapeutic anti-infective concentrations and did not achieve the requisite pharmacodynamic exposure with current pediatric dosing recommendations. All patients achieved a microbiological response, and 95.7% achieved clinical response with active beta-lactam therapeutic drug management. These data suggest beta-lactam therapeutic drug management is a potentially valuable intervention to optimize anti-infective pharmacokinetics and the pharmacodynamic exposure. Further, these data also suggest the need for additional research in specific pediatric populations and assessing clinical outcomes associated with beta-lactam therapeutic drug management in a larger cohort of pediatric patients.