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Rationale: A guideline that both evaluates current practice and provides recommendations to address sedation, pain, and delirium management with regard for neuromuscular blockade and withdrawal is not currently available., Objective: To develop comprehensive clinical practice guidelines for critically ill infants and children, with specific attention to seven domains of care including pain, sedation/agitation, iatrogenic withdrawal, neuromuscular blockade, delirium, PICU environment, and early mobility., Design: The Society of Critical Care Medicine Pediatric Pain, Agitation, Neuromuscular Blockade, and Delirium in critically ill pediatric patients with consideration of the PICU Environment and Early Mobility Guideline Taskforce was comprised of 29 national experts who collaborated from 2009 to 2021 via teleconference and/or e-mail at least monthly for planning, literature review, and guideline development, revision, and approval. The full taskforce gathered annually in-person during the Society of Critical Care Medicine Congress for progress reports and further strategizing with the final face-to-face meeting occurring in February 2020. Throughout this process, the Society of Critical Care Medicine standard operating procedures Manual for Guidelines development was adhered to., Methods: Taskforce content experts separated into subgroups addressing pain/analgesia, sedation, tolerance/iatrogenic withdrawal, neuromuscular blockade, delirium, PICU environment (family presence and sleep hygiene), and early mobility. Subgroups created descriptive and actionable Population, Intervention, Comparison, and Outcome questions. An experienced medical information specialist developed search strategies to identify relevant literature between January 1990 and January 2020. Subgroups reviewed literature, determined quality of evidence, and formulated recommendations classified as "strong" with "we recommend" or "conditional" with "we suggest." Good practice statements were used when indirect evidence supported benefit with no or minimal risk. Evidence gaps were noted. Initial recommendations were reviewed by each subgroup and revised as deemed necessary prior to being disseminated for voting by the full taskforce. Individuals who had an overt or potential conflict of interest abstained from relevant votes. Expert opinion alone was not used in substitution for a lack of evidence., Results: The Pediatric Pain, Agitation, Neuromuscular Blockade, and Delirium in critically ill pediatric patients with consideration of the PICU Environment and Early Mobility taskforce issued 44 recommendations (14 strong and 30 conditional) and five good practice statements., Conclusions: The current guidelines represent a comprehensive list of practical clinical recommendations for the assessment, prevention, and management of key aspects for the comprehensive critical care of infants and children. Main areas of focus included 1) need for the routine monitoring of pain, agitation, withdrawal, and delirium using validated tools, 2) enhanced use of protocolized sedation and analgesia, and 3) recognition of the importance of nonpharmacologic interventions for enhancing patient comfort and comprehensive care provision., Competing Interests: Drs. Smith and Berkenbosch were responsible for the adjudication of any conflicts of interest for this guideline. The following relevant disclosures were provided for consideration. Dr. Srinivasan authored “Conversion from prolonged intravenous fentanyl infusion to enteral methadone in critically ill children,” World Journal of Clinical Pediatrics (May 2017). Dr. Almgren authored “Pharmacological Strategies for Decreasing Opioid Therapy and Management of Side Effects From Chronic Use”, Children (2018) and “Multidisciplinary Pain Management for Pediatric Patients with Acute and Chronic Pain: A Foundational Treatment Approach When Prescribing Opioids,” Children (2019). Dr. Grant was a lead author for the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) Study Investigators (2016) and for “Dexmedetomidine Use in Critically-Ill Children with Acute Respiratory Failure,” Pediatric Critical Care Medicine. Dr. deAlmeida was a contributing author on “Delirium in Critically Ill Children: An International Point Prevalence Study,” Critical Care Medicine (2017). Dr. Simone is a lead author for “Analgesia, Sedation, Paralytics, and Opioid Syndrome (2021); Pediatric Acute Care. A Guide for Interprofessional Practice, second Edition (2019); Delirium and Pharmacologic Treatment in Critically Ill Children: A Retrospective Matched Cohort Study,” Journal of Pediatric Pharmacologic and Therapeutics (2017). “Implementation of an ICU Bundle: An Interprofessional Quality Improvement Project to Enhance Delirium Management and Monitor Delirium Prevalence in a Single PICU,” Pediatric Critical Care Medicine (2017). Dr. Su was a lead author for “Pharmacokinetics of Dexmedetomidine in Infants and Children After Orthotopic Liver Transplantation,” Anesthesia Analog (2018). Dr. Traube was a lead author on “Detection and Management of Delirium in the Neonatal Unit: A Case Series,” Pediatrics (2016); “Prospective Study to Establish the German version of the CAPD for the Assessment of Delirium in Children Undergoing Intensive Care” (German), Monatsschrift Kinderheilkunde (2016); “Cost Associated With Pediatric Delirium in the ICU,” Critical Care Medicine (2016); “Validity of the Richmond Agitation-Sedation Scale (RASS) in Critically Ill Children,” Journal of Intensive Care (2016); “Sedation, Analgesia, and Paralysis During Mechanical Ventilation of Premature Infants,”(2017), “Patterns of Postoperative Delirium in Children,” Pediatric Critical Care Medicine (2017); “Delirium in Children After Cardiac Bypass Surgery,” Pediatric Critical Care Medicine (2017); “Delirium in Critically Ill Children: An International Point Prevalence Study,”Critical Care Medicine (2017); “Delirium and Mortality in Critically Ill Children: Epidemiology and Outcomes of Pediatric Delirium,” Critical Care Medicine (2017); “Iatrogenic Withdrawal Syndrome or Undiagnosed Delirium?,” Critical Care Medicine (2017); “‘The Times They Are A-Changin’: Universal Delirium Screening in Pediatric Critical Care,” Pediatric Critical Care Medicine (2017); “Quality Improvement Initiative to Reduce Pediatric Intensive Care Unit Noise Pollution With the Use of a Pediatric Delirium Bundle,” Journal of Intensive Care Medicine (2017); “Delirium in Pediatric Critical Care,” Pediatric Clinics of North America (2017); “Delirium in the Pediatric Cardiac Extracorporeal Membrane Oxygenation Patient Population: A Case Series,” Pediatric Critical Care Medicine (2017); “Delirium in Hospitalized Children with Cancer: Incidence and Associated Risk Factors,” The Journal of Pediatrics (2017); “Provider Beliefs Regarding Early Mobilization in the Pediatric Intensive Care Unit,” Journal of Pediatric Nursing (2018); “Identify Delirium, Then Investigate for Underlying Etiology,” Pediatric Critical Care Medicine (2018); “Consensus Report by PALISI and PBMTC Joint Working Committees, Supportive Care Guidelines for Management of VOD in Children and Adolescents; Part 3: Focus on Cardio-Respiratory Dysfunction, Infections, Liver Dysfunction and Delirium,” Biology of Blood and Marrow Transplantation (2018); “Delirium is a Common and Early Finding in Patients in the Pediatric Cardiac Intensive Care Unit,” The Journal of Pediatrics (2018); “Delirium Upon Presentation to the Pediatric Emergency Department: A Case Series,” Pediatric Emergency Care (2018); “Benzodiazepines and Development of Delirium in Critically Ill Children: Estimating the Causal Effect,” Critical Care Medicine (2018); “Association Between Transfusion of RBCs and Subsequent Development of Delirium in Critically Ill Children,” Pediatric Critical Care Medicine (2018); “All Delirium May Not Be Created Equal: Consideration of Differential Effects of Delirium Based Upon Underlying Etiology,” Pediatric Critical Care Medicine (2018); “Risk Factors for the Development of Postoperative Delirium in Pediatric Intensive Care Patients,” Pediatric Critical Care Medicine (2018); “Management Guidelines For Paediatric Patients Receiving Chimeric Antigen Receptor T Cell Therapy,” Nature Reviews Clinical Oncology (2019); and “A Systematic Approach to Family Engagement: Feasibility Pilot of a Pediatric Delirium Management And Prevention Toolkit,” Palliative and Supportive Care (2019). Stacey Williams was lead author for “The Preschool Confusion Assessment Method for the ICU: Valid and Reliable Delirium Monitoring for Critically Ill Infants and Children,” Critical Care Medicine(2016). The remaining authors have disclosed that they do not have any potential conflicts of interest. Taskforce content experts separated into subgroups addressing pain/analgesia, sedation, tolerance/iatrogenic withdrawal, neuromuscular blockade, delirium, PICU environment (family presence and sleep hygiene), and early mobility. Subgroups created descriptive and actionable Population, Intervention, Comparison, and Outcome questions. An experienced medical information specialist developed search strategies to identify relevant literature between January 1990 and January 2020. Subgroups reviewed literature, determined quality of evidence, and formulated recommendations classified as “strong” with “we recommend” or “conditional” with “we suggest.” Good practice statements were used when indirect evidence supported benefit with no or minimal risk. Evidence gaps were noted. Initial recommendations were reviewed by each subgroup and revised as deemed necessary prior to being disseminated for voting by the full taskforce. Individuals who had an overt or potential conflict of interest abstained from relevant votes. Expert opinion alone was not used in substitution for a lack of evidence., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Cardiac function and dysfunction are important in the clinical outcomes of sepsis and septic shock. Cardiac dysfunction is not a single entity, but is a broad spectrum of syndromes that result in biventricular cardiac dysfunction manifested by both systolic and diastolic dysfunction and is influenced by cardiac loading conditions (ie, preload and afterload). Elucidating the underlying pathophysiology has proved to be complex. This article emphasizes the underlying pathophysiology of cardiac dysfunction and explores recent evidence related to diagnosis, including the utility of biomarkers, the role of echocardiography, and management goals and treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The ability to synthesize and propagate genetic information encoded in the framework of xeno-nucleic acid (XNA) polymers would inform a wide range of topics from the origins of life to synthetic biology. While directed evolution has produced examples of engineered polymerases that can accept XNA substrates, these enzymes function with reduced activity relative to their natural counterparts. Here, we describe a biochemical strategy that enables the discovery of engineered polymerases with improved activity for a given unnatural polymerase function. Our approach involves identifying specificity determining residues (SDRs) that control polymerase activity, screening mutations at SDR positions in a model polymerase scaffold, and assaying key gain-of-function mutations in orthologous protein architectures. By transferring beneficial mutations between homologous protein structures, we show that new polymerases can be identified that function with superior activity relative to their starting donor scaffold. This concept, which we call scaffold sampling, was used to generate engineered DNA polymerases that can faithfully synthesize RNA and TNA (threose nucleic acid), respectively, on a DNA template with high primer-extension efficiency and low template sequence bias. We suggest that the ability to combine phenotypes from different donor and recipient scaffolds provides a new paradigm in polymerase engineering where natural structural diversity can be used to refine the catalytic activity of synthetic enzymes.

In vitro selection technologies are important tools for identifying high affinity peptides to proteins of broad medical and biological interest. However, the technological advances that have made it possible to generate long lists of candidate peptides have far outpaced our ability to characterize the binding properties of individual peptides. Here, we describe a low cost strategy to rapidly synthesize, purify, screen, and characterize peptides for high binding affinity. Peptides are assayed in a 96-well dot blot apparatus using membranes that enable partitioning of bound and unbound peptide-protein complexes. We have validated the binding affinity constants produced by this method using known peptide ligands and applied this process to discover five new peptides with nanomolar affinity to human α-thrombin. Given the need for new analytical tools that can accelerate peptide discovery and characterization, we feel that this approach would be useful to a wide range of technologies that utilize high affinity peptides.

Object: For patients with glioblastoma multiforme, median survival time is approximately 14 months. Longer progression-free and overall survival times correlate with gross-total resection of tumor. The ability to identify tumor cells intraoperatively could result in an increased percentage of tumor resected and thus increased patient survival times. Available labeling methods rely on metabolic activity of tumor cells; thus, they are more robust in high-grade tumors, and their utility in low-grade tumors and metastatic tumors is not clear. The authors demonstrate intraoperative identification of tumor cells by using labeled tumor-specific antibodies., Methods: GL261 mouse glioma cells exhibit high expression of a membrane-bound protein called second tyrosinase-related protein (TRP-2). The authors used these cells to establish an intracranial, immunocompetent model of malignant glioma. Antibodies to TRP-2 were labeled by using Alexa Fluor 488 fluorescent dye and injected into the tail vein of albino C57BL/6 mice. After 24 hours, a craniotomy was performed and the tissue was examined in vivo by using an Optiscan 5.1 handheld portable confocal fiber-optic microscope. Tissue was examined ex vivo by using a Pascal 5 scanning confocal microscope., Results: Labeled tumor cells were visible in vivo and ex vivo under the respective microscopes., Conclusions: Fluorescently labeled tumor-specific antibodies are capable of binding and identifying tumor cells in vivo, accurately and specifically. The development of labeled markers for the identification of brain tumors will facilitate the use of intraoperative fluorescence microscopy as a tool for increasing the extent of resection of a broad variety of intracranial tumors.

Seizures, particularly first onset seizures in adults, are a diagnostic hallmark of brain tumors (Giglio and Villano, 2010). Unfortunately, malignant brain tumors are almost uniformly fatal due, in part, to the limitations of available therapies. Improvement in the survival of brain cancer patients requires the design of new therapeutic modalities including those that enhance currently available therapies. One potential strategy is to exploit differences in metabolic regulation between normal cells and tumor cells through dietary approaches. Previous studies have shown that a high-fat, low-carbohydrate ketogenic diet (KD) extends survival in animal models of glioma; however, the mechanism for this effect is not entirely known. We examined the effects of an experimental KD on a mouse model of glioma, and compared patterns of gene expression in tumors versus contralateral non-tumor containing brain from animals fed either a KD or a standard diet. We found that the KD reduced reactive oxygen species (ROS) production in tumor cells. Gene expression profiling demonstrated that the KD induces an overall reversion to expression patterns seen in non-tumor specimens, and a number of genes involved in modulating ROS levels and oxidative stress were altered in tumor cells. In addition, there was reduced expression of genes involved in signal transduction from growth factors known to be involved in glioma growth. These results suggest that the anti-tumor effect of the KD is multifactorial, and elucidation of genes whose expression is altered will help identify mechanisms through which ketones inhibit tumor growth, reduce seizure activity and provide neuroprotection., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: Sepsis is common in children and often results in cardiac dysfunction. Assessment of patients with sepsis-associated myocardial depression using ejection fraction and fractional shortening with conventional echocardiography is load dependent and often reveals cardiac dysfunction only after clinical deterioration has occurred. Speckle tracking imaging is a novel technology that can assess deformation and strain by tracking displacement of acoustic markers in the myocardium. We hypothesize that speckle tracking imaging will detect cardiac impairments during sepsis that are not appreciated by conventional echocardiography., Design: Retrospective, observational study., Setting: A large, tertiary-care pediatric intensive care unit., Patients: Fifteen pediatric patients with septic shock, and 30 age- and gender-matched healthy controls., Interventions: Transthoracic echocardiograms from subjects with septic shock (by American College of Chest Physicians/Society of Critical Care Medicine consensus criteria) and controls were evaluated. Speckle tracking imaging was used to obtain tissue displacement, velocity, strain, and strain rate in radial, longitudinal, and circumferential planes. Ejection fraction and fractional shortening were determined by conventional methods. Comparisons between groups were made using a paired t test., Measurements and Main Results: Compared to control subjects, children with septic shock demonstrated impaired myocardial performance as quantified by speckle tracking imaging. Significant differences were seen in circumferential and longitudinal strain (p < .001), strain rate (p < .05), radial displacement (p < .001), and rotational velocity and displacement (p < .01). There was no significant difference in ejection fraction and fractional shortening between septic patients and controls., Conclusions: Speckle tracking imaging detected a number of significantly impaired measures of ventricular performance in children with sepsis, not appreciated by conventional echocardiography. This technology may improve our understanding and identification of myocardial depression in the critically ill septic child.

Introduction: The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal® (KC) is a nutritionally complete, commercially available 4:1 (fat:carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas., Methods: We used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2×4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging., Results: Animals fed KC had elevated levels of β-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days., Conclusions: KC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas.

Background: Paediatric cardiac services are poorly developed or totally absent in underdeveloped countries. Institutions, foundations and interested individuals in those nations in which sophisticated paediatric cardiac surgery is practised have the ability to alleviate this problem by sponsoring paediatric cardio-surgical missions to provide care, and train local caregivers in developing, transitional, and third world countries. The ultimate benefit of such a programme is to improve the surgical abilities of the host institution. The purpose of this report is to present the impact of our programme over a period of 14 years., Methods: We specifically reviewed our database of patients from our missions, our team lists, surgical results, and the number and type of personnel trained in the institutions that we have assisted. In order for the institution to be entered into the study, the foundation had to provide at least 2 months of training. In addition, the institution had to respond to a simple questionnaire concerning the number and types of surgery performed at their facility before and after intervention by the foundation., Results: We made 140 trips to 27 institutions in 19 countries, with 12 of the visited institutions qualifying for inclusion. Of these, 9 institutions reported an increase in the number and complexity of cases currently being performed in their facility since the team intervened. This goal had not been accomplished in 3 institutions. The reasons for failure included the economic situation of the country, hospital and national politics, personality conflicts, and continued lack of hardware and disposables., Conclusions: Paediatric cardiac service assistance can improve local services. A significant commitment is required by all parties involved.