https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=10319&context=open_access_pubs

ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment of patients up to age 25 years with relapsed or refractory B cell acute lymphoblastic leukemia years "?>and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.

ASBMT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Importance Protocolized sedation improves clinical outcomes in critically ill adults, but its effect in children is unknown Objective To determine whether critically ill children managed with a nurse-implemented, goal-directed sedation protocol experience fewer days of mechanical ventilation than patients receiving usual care Design, Setting, and Participants Cluster randomized trial conducted in 31 US pediatric intensive care units (PICUs) A total of 2449 children (mean age, 47 years; range, 2 weeks to 17 years) mechanically ventilated for acute respiratory failure were enrolled in 2009-2013 and followed up until 72 hours after opioids were discontinued, 28 days, or hospital discharge Intervention Intervention PICUs (17 sites; n = 1225 patients) used a protocol that included targeted sedation, arousal assessments, extubation readiness testing, sedation adjustment every 8 hours, and sedation weaning Control PICUs (14 sites; n = 1224 patients) managed sedation per usual care Main Outcomes and Measures The primary outcome was duration of mechanical ventilation Secondary outcomes included time to recovery from acute respiratory failure, duration of weaning from mechanical ventilation, neurological testing, PICU and hospital lengths of stay, in-hospital mortality, sedation-related adverse events, measures of sedative exposure (wakefulness, pain, and agitation), and occurrence of iatrogenic withdrawal Results Duration of mechanical ventilation was not different between the 2 groups (intervention: median, 65 [IQR, 41-112] days; control: median, 65 [IQR, 37-121] days) Sedation-related adverse events including inadequate pain and sedation management, clinically significant iatrogenic withdrawal, and unplanned endotracheal tube/invasive line removal were not significantly different between the 2 groups Intervention patients experienced more postextubation stridor (7% vs 4%; P  = 03) and fewer stage 2 or worse immobility-related pressure ulcers ( P  = 001) In exploratory analyses, intervention patients had fewer days of opioid administration (median, 9 [IQR, 5-15] days vs 10 [IQR, 4-21] days; P  = 01), were exposed to fewer sedative classes (median, 2 [IQR, 2-3] classes vs 3 [IQR, 2-4] classes; P P  = 004) than control patients, respectively; however, intervention patients had more days with any report of a pain score ≥4 (median, 50% [IQR, 27%-67%] of days vs 23% [IQR, 0%-46%] of days; P P  = 003), respectively Conclusions and Relevance Among children undergoing mechanical ventilation for acute respiratory failure, the use of a sedation protocol compared with usual care did not reduce the duration of mechanical ventilation Exploratory analyses of secondary outcomes suggest a complex relationship among wakefulness, pain, and agitation Trial Registration clinicaltrialsgov Identifier:NCT00814099

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Protocolized Sedation vs Usual Care in Pediatric Patients Mechanically Ventilated for Acute Respiratory Failure: A Randomized Clinical Trial

Background
This position statement provides clinical recommendations for the assessment of pain, level of sedation, iatrogenic withdrawal syndrome and delirium in critically ill infants and children. Admission to a neonatal or paediatric intensive care unit (NICU, PICU) exposes a child to a series of painful and stressful events. Accurate assessment of the presence of pain and non-pain-related distress (adequacy of sedation, iatrogenic withdrawal syndrome and delirium) is essential to good clinical management and to monitoring the effectiveness of interventions to relieve or prevent pain and distress in the individual patient.

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Clinical recommendations for pain, sedation, withdrawal and delirium assessment in critically ill infants and children: an ESPNIC position statement for healthcare professionals

Objectives:Delirium occurs frequently in adults and is an independent predictor of mortality. However, the epidemiology and outcomes of pediatric delirium are not well-characterized. The primary objectives of this study were to describe the frequency of delirium in critically ill children, its durat

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Delirium and Mortality in Critically Ill Children: Epidemiology and Outcomes of Pediatric Delirium.

Objective:To determine validity and reliability of the Cornell Assessment of Pediatric Delirium, a rapid observational screening tool.Design:Double-blinded assessments were performed with the Cornell Assessment of Pediatric Delirium completed by nursing staff in the PICU. These ratings were compared

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Cornell Assessment of Pediatric Delirium: A Valid, Rapid, Observational Tool for Screening Delirium in the PICU*

Ventricular tachycardia in pediatric emergency department patients is a high-risk, low-frequency event well suited for education through simulation. This technical report describes a simulation-based curriculum for Pediatric Emergency Medicine fellows and senior residents involving the evaluation and management of a 10-year-old female presenting with palpitations who is ultimately diagnosed with Belhassen tachycardia. The curriculum highlights the features that differentiate Belhassen tachycardia (idiopathic left posterior fascicular ventricular tachycardia) from supraventricular or other tachycardias, building upon foundational pediatric resuscitation skills and Pediatric Advanced Life Support (PALS) algorithms for advanced learners.

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Julie Augenstein

Papers

Cornell Assessment of Pediatric Delirium: A Valid, Rapid, Observational Tool for Screening Delirium in the PICU*

Belhassen Tachycardia in a Pediatric Patient: A Simulation for Pediatric Emergency Medicine Fellows