Adam S. Himebauch

Implementation of a pediatric critical care focused bedside ultrasound training program in a large academic PICU.

Objectives: To determine the feasibility and describe the process of implementing a pediatric critical care bedside ultrasound program in a large academic PICU and to evaluate the impact of bedside ultrasound on clinical management. Design: Retrospective case series, description of program implementation. Setting: Single-center quaternary noncardiac PICU in a children’s hospital. Patients: Consecutive patients from January 22, 2012, to July 22, 2012, with bedside ultrasounds performed and interpreted by pediatric critical care practitioners. Interventions: A pediatric critical care bedside ultrasound program consisting of a 2-day immersive course followed by clinical performance with internal quality assurance review was implemented. Studies performed in the PICU following training were documented and reviewed against reference standards including subspecialist-performed ultrasound or clinical response. Measurements and Main Results: Seventeen critical care faculties and eight fellows recorded 201 bedside ultrasound studies over 6 months in defined core applications: 57 procedural (28%), 76 hemodynamic (38%), 35 thoracic (17%), and 33 abdominal (16%). A quality assurance review identified 23 studies (16% of all nonprocedural studies) as critical (affected clinical management or gave valuable information). Forty-eight percent of those studies (11/23) were within the hemodynamic core. The proportion of critical studies were not significantly different across the applications (hemodynamic, 11/76 [15%] vs thoracic and abdominal, 12/68 [18%]; p = 0.65). Examples of critical studies include evidence of tamponade secondary to pleural effusions, identification of pulmonary hypertension, hemodynamic assessment before tracheal intubation, recognition of hypovolemia and systemic vascular resistance abnormalities, determination of pneumothorax, location of chest tube and urinary catheter, and differentiation of pleural fluid from pulmonary consolidation. Conclusions: Implementation of a critical care bedside ultrasound program for critical care providers in a large academic PICU is feasible. Bedside ultrasound evaluation and interpretation by intensivists affected the management of critically ill children.

Skeletal muscle and plasma concentrations of cefazolin during cardiac surgery in infants

OBJECTIVE To describe the pharmacokinetics and tissue disposition of prophylactic cefazolin into skeletal muscle in a pediatric population undergoing cardiac surgery. METHODS The subjects included 12 children, with a median age of 146 days (interquartile range, 136-174) and median weight of 5.5 kg (interquartile range, 5.2-7.3) undergoing cardiac surgery and requiring cardiopulmonary bypass with or without deep hypothermic circulatory arrest. Institutional cefazolin at standard doses of 25 mg/kg before incision and 25 mg/kg in the bypass prime solution were administered. Serial plasma and skeletal muscle microdialysis samples were obtained intraoperatively and the unbound cefazolin concentrations measured. Noncompartmental pharmacokinetic analyses were performed and the tissue disposition evaluated. RESULTS After the first dose of cefazolin, the skeletal muscle concentrations peaked at a median microdialysis collection interval of 30 to 38.5 minutes. After the second dose, the peak concentrations were delayed a median of 94 minutes in subjects undergoing deep hypothermic circulatory arrest. Skeletal muscle exposure to cefazolin measured by the area under concentration time curve 0-last measurement was less in the subjects who underwent deep hypothermic circulatory arrest than in those who received cardiopulmonary bypass alone (P = .04). The skeletal muscle concentrations of cefazolin exceeded the goal concentrations for methicillin-sensitive Staphylococcus aureus prophylaxis; however, the goal concentrations for gram-negative pathogens associated with surgical site infections were achieved only 42.1% to 84.2% and 0% to 11.2% of the intraoperative time in subjects undergoing cardiopulmonary bypass alone or deep hypothermic circulatory arrest, respectively. CONCLUSIONS This cefazolin dosing strategy resulted in skeletal muscle concentrations that are likely not effective for surgical prophylaxis against gram-negative pathogens but are effective against methicillin-sensitive S aureus in infants undergoing cardiac surgery.

Methods for pharmacokinetic analysis in young children

Introduction: Pediatric physiology and disease states are often complex and are distinct from adults. Pediatric clinicians and scientists, as well as governmental regulators, are increasingly concerned with the necessity to optimize clinical pharmacological study design to achieve appropriate drug-dosing practices for various pediatric populations. Areas covered: There are significant challenges in clinical trial design, implementation and analysis that are unique to pediatric populations. Innovative techniques of sample preparation and analysis of pharmacokinetic (PK) studies as well as modern methods of data analysis, including PK modeling and simulation, that address some of these challenges are reviewed along with recent examples from the literature. Expert opinion: There have been clear and exciting advances in the understanding of pediatric clinical pharmacology in the areas of clinical trial design and sample analysis, as well as PK and pharmacodynamic modeling and simulation. Further advances require collaboration and interdisciplinary efforts from multiple specialties in both academia and industry. Ideally, these efforts will then not only provide informed and individualized dosing for pediatric patients but will also provide new methods and algorithms for broader use of new pharmacotherapeutic agents or applications.

Hemodynamic Bedside Ultrasound Image Quality and Interpretation After Implementation of a Training Curriculum for Pediatric Critical Care Medicine Providers.

Objective: Bedside ultrasound for hemodynamic evaluation in critically ill children is increasingly recognized as an important skill for pediatric critical care medicine providers. Our institution implemented a training curriculum leading to institutional credentialing for pediatric critical care providers in nonprocedural bedside ultrasound core applications. We hypothesized that hemodynamic studies performed or supervised by credentialed providers (credentialed providers group) have better image quality and greater accuracy in interpretation than studies performed by non–credentialed providers without supervision (non–credentialed providers group). Design: Retrospective descriptive study. Setting: Single-center tertiary non-cardiac 55-bed PICU in a children’s hospital. Patients: Patients from October 2013 to January 2015, with hemodynamic bedside ultrasound performed and interpreted by pediatric critical care providers exposed to bedside ultrasound training. Interventions: A cardiologist blinded to performer scored hemodynamic bedside ultrasound image quality for five core cardiac views (excellent = 3, good = 2, fair = 1, unacceptable = 0; median = quality score) and interpretation within 5 hemodynamic domains (agreement = 3, minor disagreement = 2, major disagreement = 1; median = interpretation score), as well as a global assessment of interpretation. Measurements and Main Results: Eighty-one studies (45 in the credentialed providers group and 36 in the non–credentialed providers group) were evaluated. There was no statistically significant difference in quality score between groups (median: 1.4 [interquartile range: 0.8–1.8] vs median: 1.2 [interquartile range: 0.75–1.6]; p = 0.14]. Studies in the credentialed providers group had higher interpretation score than those in the non–credentialed providers group (median: 3 [interquartile range: 2.5–3) vs median: 2.67 [interquartile range: 2.25–3]; p = 0.04). Major disagreement between critical care provider and cardiology review occurred in 25 of 283 hemodynamic domains assessed (8.8%), with no statistically significant difference between credentialed providers and non–credentialed providers groups (6.1% vs 11.9%; p = 0.12). Conclusion: Hemodynamic bedside ultrasound performed or supervised by credentialed pediatric critical care providers had more accurate interpretation than studies performed by unsupervised non–credentialed providers. A rigorous pediatric critical care medicine bedside ultrasound credentialing program can train intensivists to attain adequate images and interpret those images appropriately.

Pharmacotherapy during pediatric extracorporeal membrane oxygenation: a review

ABSTRACT Introduction: Pediatric critical illness and associated alterations in organ function can change drug pharmacokinetics (PK). Extracorporeal membrane oxygenation (ECMO), a life-saving therapy for severe cardiac and/or respiratory failure, causes additional PK alterations that affect drug disposition. Areas covered: The purposes of this review are to discuss the PK changes that occur during ECMO, the associated therapeutic implications, and to review PK literature relevant to pediatric ECMO. We discuss various classes of drugs commonly used for pediatric patients on ECMO, including sedatives, analgesics, antimicrobials and cardiovascular drugs. Finally, we discuss future areas of research and recommend strategies for future pediatric ECMO pharmacologic investigations. Expert opinion: Clinicians caring for pediatric patients treated with ECMO must have an understanding of PK alterations that could lead to either therapeutic failures or increased drug toxicity during this life-saving therapy. Limited data currently exist for optimal drug dosing in pediatric populations who are treated with ECMO. While there are clear challenges to conducting and analyzing data associated with clinical pharmacokinetic-pharmacodynamic studies of children on ECMO, we present techniques to address these challenges. Improved understanding of the physiology and drug disposition during ECMO combined with PK-PD modeling will allow for more adaptable and individualized dosing schemes.

Poor outcome with hematopoietic stem cell transplantation for bone marrow failure and MDS with severe MIRAGE syndrome phenotype

Key Points Success of hematopoietic stem cell transplantation for MIRAGE syndrome may be limited by syndrome-specific comorbidities. SAMD9 mutations associated with MIRAGE syndrome are a newly described cause of congenital amegakaryocytic thrombocytopenia.

Skeletal muscle and plasma concentrations of cefazolin during complex paediatric spinal surgery

BACKGROUND Surgical site infections (SSIs) can have devastating consequences for children who undergo spinal instrumentation. Prospective evaluations of prophylactic cefazolin in this population are limited. The purpose of this study was to describe the pharmacokinetics and skeletal muscle disposition of prophylactic cefazolin in a paediatric population undergoing complex spinal surgery. METHODS This prospective pharmacokinetic study included 17 children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, with a median age of 13.8 [interquartile range (IQR) 13.4-15.4] yr and a median weight of 60.6 (IQR 50.8-66.0) kg. A dosing strategy consistent with published guidelines was used. Serial plasma and skeletal muscle microdialysis samples were obtained during the operative procedure and unbound cefazolin concentrations measured. Non-compartmental pharmacokinetic analyses were performed. The amount of time that the concentration of unbound cefazolin exceeded the minimal inhibitory concentration for bacterial growth for selected SSI pathogens was calculated. RESULTS Skeletal muscle concentrations peaked at a median of 37.6 (IQR 26.8-40.0) µg ml(-1) within 30-60 min after the first cefazolin 30 mg kg(-1) dose. For patients who received a second 30 mg kg(-1) dose, the peak concentrations reached a median of 40.5 (IQR 30.8-45.7) µg ml(-1) within 30-60 min. The target cefazolin concentrations for SSI prophylaxis for meticillin-sensitive Staphylococcus aureus (MSSA) and Gram-negative pathogens were exceeded in skeletal muscle 98.9 and 58.3% of the intraoperative time, respectively. CONCLUSIONS For children with adolescent idiopathic scoliosis undergoing posterior spinal fusion, the cefazolin dosing strategy used in this study resulted in skeletal muscle concentrations that were likely not to be effective for intraoperative SSI prophylaxis against Gram-negative pathogens.

A pilot and feasibility study of the plasma and tissue pharmacokinetics of cefazolin in an immature porcine model of pediatric cardiac surgery

Surgical site infection (SSI) prevention for children with congenital heart disease is imperative and methods to assess and evaluate the tissue concentrations of prophylactic antibiotics are important to help maximize these efforts.

Plasma and Tissue Pharmacokinetics of Cefazolin in an Immature Porcine Modelof Pediatric Cardiac Surgery

Background: Surgical Site Infection (SSI) prevention for children with congenital heart disease is imperative and methods to assess and evaluate the tissue concentrations of prophylactic antibiotics are important to help maximize these efforts. The purpose of this study was to determine the plasma and tissue concentrations of standard-of-care peri-operative cefazolin dosing in an immature porcine model of cardiac surgery and cardiopulmonary bypass. Methods: Piglets (3-5 days old) underwent either median sternotomy (MS) or cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB+DHCA) and received standard of care prophylactic cefazolin for the procedures. Serial plasma and microdialysis sampling of skeletal muscle and subcutaneous tissue adjacent to the surgical site was performed. Cefazolin concentrations were measured, non-compartmental pharmacokinetic analyses were performed, and tissue penetration of cefazolin was assessed. Results: Following the first intravenous dose, maximal cefazolin concentrations for plasma and tissue samples were similar between groups with peak tissue concentrations 15-30 minutes after administration. After the second cefazolin dose given with initiation of CPB, total plasma cefazolin concentrations remained relatively constant until the end of DHCA and then decreased while muscle and subcutaneous unbound cefazolin concentrations showed a second peak during or after rewarming. For the MS group, 60-67% of the intraoperative time showed tissue cefazolin concentrations greater than16 μg/mL while this percentage was 78-79% for the CPB+DHCA group. There was less tissue penetration of cefazolin in the group that underwent CBP+DHCA (P=0.03). Conclusions: The cefazolin dosing used in this study achieves plasma and tissue concentrations that should be effective against methicillin-sensitive Staphylococcus aureus but may not be effective against some gram-negative pathogens. The timing of cefazolin administration prior to incision and a second dose given during cardiopulmonary bypass may be important factors for achieving goal tissue concentrations.

Characterization of Thoracic Pathophysiologic Conditions in Patients Receiving High‐Frequency Oscillatory Ventilation: Pediatric Experience

High‐frequency oscillatory ventilation (HFOV) is a mode of mechanical ventilation used in severe pediatric respiratory failure. Thoracic ultrasound (US) is a powerful tool for diagnosing acute pathophysiologic conditions during spontaneous respiration and conventional noninvasive and invasive mechanical ventilation. High‐frequency oscillatory ventilation differs from conventional modes of ventilation in that it does not primarily use bulk flow delivery for gas exchange but, rather, a number of alternative mechanisms as the result of pressure variations oscillating around a constant distending pressure. Thoracic US has not been well described in patients receiving HFOV, and it is unclear whether the US findings for assessing thoracic pathophysiologic conditions during conventional ventilation are applicable to patients receiving HFOV. We discuss the similarities and differences of thoracic US findings in patients who are spontaneously breathing or receiving conventional ventilation compared to those in patients receiving HFOV.