Publications by authors named "Ira M Cheifetz"

133 Publications

Early Neuromuscular Blockade in Moderate-to-Severe Pediatric Acute Respiratory Distress Syndrome.

Crit Care Med 2022 Jan 6. Epub 2022 Jan 6.

Department of Family and Community Health, School of Nursing, University of Pennsylvania, Philadelphia, PA.

Objectives: The use of neuromuscular blocking agents (NMBAs) in pediatric acute respiratory distress syndrome (PARDS) is common but unsupported by efficacy data. We sought to compare the outcomes between patients with moderate-to-severe PARDS receiving continuous NMBA during the first 48 hours of endotracheal intubation (early NMBA) and those without.

Design: Secondary analysis of data from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial, a pediatric multicenter cluster randomized trial of sedation.

Setting: Thirty-one PICUs in the United States.

Patients: Children 2 weeks to 17 years receiving invasive mechanical ventilation (MV) for moderate-to-severe PARDS (i.e., oxygenation index >= 8 and bilateral infiltrates on chest radiograph on days 0-1 of endotracheal intubation).

Interventions: NMBA for the entire duration of days 1 and 2 after intubation.

Measurements And Main Results: Among 1,182 RESTORE patients with moderate-to-severe PARDS, 196 (17%) received early NMBA for a median of 50.0% ventilator days (interquartile range, 33.3-60.7%). The propensity score model predicting the probability of receiving early NMBA included high-frequency oscillatory ventilation on days 0-2 (odds ratio [OR], 7.61; 95% CI, 4.75-12.21) and severe PARDS on days 0-1 (OR, 2.16; 95% CI, 1.50-3.12). After adjusting for risk category, early use of NMBA was associated with a longer duration of MV (hazard ratio, 0.57; 95% CI, 0.48-0.68; p < 0.0001), but not with mortality (OR, 1.62; 95% CI, 0.92-2.85; p = 0.096) compared with no early use of NMBA. Other outcomes including cognitive, functional, and physical impairment at 6 months post-PICU discharge were similar. Outcomes did not differ when comparing high versus low NMBA usage sites or when patients were stratified by baseline PaO2/FIO2 less than 150.

Conclusions: Early NMBA use was associated with a longer duration of MV. This propensity score analysis underscores the need for a randomized controlled trial in pediatrics.
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http://dx.doi.org/10.1097/CCM.0000000000005426DOI Listing
January 2022

Respiratory Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference.

Pediatrics 2022 01;149(1 Suppl 1):S48-S52

Division of Pediatric Critical Care Medicine, Departments of Pediatrics and Public Health Science, The Pennsylvania State University and Hershey Children's Hospital, Hershey, Pennsylvania.

Context: Respiratory dysfunction is a component of every organ failure scoring system developed, reflecting the significance of the lung in multiple organ dysfunction syndrome. However, existing systems do not reflect current practice and are not consistently evidence based.

Objective: We aimed to review the literature to identify the components of respiratory failure associated with outcomes in children, with the purpose of developing an operational and evidence-based definition of respiratory dysfunction.

Data Sources: Electronic searches of PubMed and Embase were conducted from 1992 to January 2020 by using a combination of medical subject heading terms and text words to define respiratory dysfunction, critical illness, and outcomes.

Study Selection: We included studies of critically ill children with respiratory dysfunction that evaluated the performance of metrics of respiratory dysfunction and their association with patient-centered outcomes. Studies in adults, studies in premature infants (≤36 weeks' gestational age), animal studies, reviews and commentaries, case series with sample sizes ≤10, and studies not published in English in which we were unable to determine eligibility criteria were excluded.

Data Extraction: Data were abstracted into a standard data extraction form.

Results: We provided binary (no or yes) and graded (no, nonsevere, or severe) definitions of respiratory dysfunction, prioritizing oxygenation and respiratory support. The proposed criteria were approved by 82% of members in the first round, with a score of 8 of 9 (interquartile range 7-8).

Limitations: Exclusion of non-English publications, heterogeneity across the pediatric age range, small sample sizes, and incomplete handling of confounders are limitations.

Conclusions: We propose definitions for respiratory dysfunction in critically ill children after an exhaustive literature review.
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http://dx.doi.org/10.1542/peds.2021-052888GDOI Listing
January 2022

Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Contemporary Organ Dysfunction Criteria: Executive Summary.

Pediatrics 2022 Jan;149(Supplement_1):S1-S12

Sections of Critical Care and Nephrology.

Prior criteria for organ dysfunction in critically ill children were based mainly on expert opinion. We convened the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) expert panel to summarize data characterizing single and multiple organ dysfunction and to derive contemporary criteria for pediatric organ dysfunction. The panel was composed of 88 members representing 47 institutions and 7 countries. We conducted systematic reviews of the literature to derive evidence-based criteria for single organ dysfunction for neurologic, cardiovascular, respiratory, gastrointestinal, acute liver, renal, hematologic, coagulation, endocrine, endothelial, and immune system dysfunction. We searched PubMed and Embase from January 1992 to January 2020. Study identification was accomplished using a combination of medical subject headings terms and keywords related to concepts of pediatric organ dysfunction. Electronic searches were performed by medical librarians. Studies were eligible for inclusion if the authors reported original data collected in critically ill children; evaluated performance characteristics of scoring tools or clinical assessments for organ dysfunction; and assessed a patient-centered, clinically meaningful outcome. Data were abstracted from each included study into an electronic data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. Consensus was achieved for a final set of 43 criteria for pediatric organ dysfunction through iterative voting and discussion. Although the PODIUM criteria for organ dysfunction were limited by available evidence and will require validation, they provide a contemporary foundation for researchers to identify and study single and multiple organ dysfunction in critically ill children.
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http://dx.doi.org/10.1542/peds.2021-052888BDOI Listing
January 2022

Nutrition in Pediatric Extracorporeal Membrane Oxygenation: A Narrative Review.

Front Nutr 2021 2;8:666464. Epub 2021 Aug 2.

Children's Intensive Care Unit, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore.

Extracorporeal membrane oxygenation (ECMO) support is increasingly utilized in quaternary pediatric intensive care units. Metabolic derangements and altered nutritional requirements are common in critically ill children supported on ECMO. However, there remains no consensus on the optimal approach to the prescription of nutrition in these patients. This narrative review aims to summarize the current medical literature on various aspects of nutrition support in pediatric patients on ECMO. These include: (1) nutritional adequacy, (2) pros and cons of feeding on ECMO, (3) enteral vs. parenteral nutrition, and (4) proposed recommendations and future directions for research in this area.
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http://dx.doi.org/10.3389/fnut.2021.666464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365758PMC
August 2021

Adherence to Lung-Protective Ventilation Principles in Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

Crit Care Med 2021 10;49(10):1779-1789

Department of Anesthesiology and Critical Care Medicine, Children's Hospital Los Angeles, Los Angeles, CA.

Objectives: To describe mechanical ventilation management and factors associated with nonadherence to lung-protective ventilation principles in pediatric acute respiratory distress syndrome.

Design: A planned ancillary study to a prospective international observational study. Mechanical ventilation management (every 6 hr measurements) during pediatric acute respiratory distress syndrome days 0-3 was described and compared with Pediatric Acute Lung Injury Consensus Conference tidal volume recommendations (< 7 mL/kg in children with impaired respiratory system compliance, < 9 mL/kg in all other children) and the Acute Respiratory Distress Syndrome Network lower positive end-expiratory pressure/higher Fio2 grid recommendations.

Setting: Seventy-one international PICUs.

Patients: Children with pediatric acute respiratory distress syndrome.

Interventions: None.

Measurements And Main Results: Analyses included 422 children. On pediatric acute respiratory distress syndrome day 0, median tidal volume was 7.6 mL/kg (interquartile range, 6.3-8.9 mL/kg) and did not differ by pediatric acute respiratory distress syndrome severity. Plateau pressure was not recorded in 97% of measurements. Using delta pressure (peak inspiratory pressure - positive end-expiratory pressure), median tidal volume increased over quartiles of median delta pressure (p = 0.007). Median delta pressure was greater than or equal to 18 cm H2O for all pediatric acute respiratory distress syndrome severity levels. In severe pediatric acute respiratory distress syndrome, tidal volume was greater than or equal to 7 mL/kg 62% of the time, and positive end-expiratory pressure was lower than recommended by the positive end-expiratory pressure/Fio2 grid 70% of the time. In multivariable analysis, tidal volume nonadherence was more common with severe pediatric acute respiratory distress syndrome, fewer PICU admissions/yr, non-European PICUs, higher delta pressure, corticosteroid use, and pressure control mode. Adherence was associated with underweight stature and cuffed endotracheal tubes. In multivariable analysis, positive end-expiratory pressure/Fio2 grid nonadherence was more common with higher pediatric acute respiratory distress syndrome severity, ventilator decisions made primarily by the attending physician, pre-ICU cardiopulmonary resuscitation, underweight stature, and age less than 2 years. Adherence was associated with respiratory therapist involvement in ventilator management and longer time from pediatric acute respiratory distress syndrome diagnosis. Higher nonadherence to tidal volume and positive end-expiratory pressure recommendations were independently associated with higher mortality and longer duration of ventilation after adjustment for confounding variables. In stratified analyses, these associations were primarily influenced by children with severe pediatric acute respiratory distress syndrome.

Conclusions: Nonadherence to lung-protective ventilation principles is common in pediatric acute respiratory distress syndrome and may impact outcome. Modifiable factors exist that may improve adherence.
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http://dx.doi.org/10.1097/CCM.0000000000005060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448899PMC
October 2021

Tracheostomy and long-term mechanical ventilation in children after veno-venous extracorporeal membrane oxygenation.

Pediatr Pulmonol 2021 09 2;56(9):3005-3012. Epub 2021 Jul 2.

Division of Pediatric Critical Care, Riley Hospital for Children, Indiana University, Indianapolis, Indiana, USA.

Objective: Our objective is to characterize the incidence of tracheostomy placement and of new requirement for long-term mechanical ventilation after extracorporeal membrane oxygenation (ECMO) among children with acute respiratory failure. We examine whether an association exists between demographics, pre-ECMO and ECMO clinical factors, and the placement of a tracheostomy or need for long-term mechanical ventilation.

Methods: A retrospective multicenter cohort study was conducted at 10 quaternary care pediatric academic centers, including children supported with veno-venous (V-V) ECMO from 2011 to 2016.

Results: Among 202 patients, 136 (67%) survived to ICU discharge. All tracheostomies were placed after ECMO decannulation, in 22 patients, with 19 of those surviving to ICU discharge (14% of survivors). Twelve patients (9% of survivors) were discharged on long-term mechanical ventilation. Tracheostomy placement and discharge on home ventilation were not associated with pre-ECMO severity of illness or pre-existing chronic illness. Patients who received a tracheostomy were older and weighed more than patients who did not receive a tracheostomy, although this association did not exist among patients discharged on home ventilation. ECMO duration was longer in those who received a tracheostomy compared with those who did not, as well as for those discharged on home ventilation, compared to those who were not.

Conclusion: The 14% rate for tracheostomy placement and 9% rate for discharge on long-term mechanical ventilation after V-V ECMO are important patient-centered findings. This study informs anticipatory guidance provided to families of patients requiring prolonged respiratory ECMO support, and lays the foundation for future research.
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http://dx.doi.org/10.1002/ppul.25546DOI Listing
September 2021

Veno-Venous Extracorporeal Membrane Oxygenation for Children With Cancer or Hematopoietic Cell Transplant: A Ten Center Cohort.

ASAIO J 2021 08;67(8):923-929

Division of Pediatric Critical Care, Riley Hospital for Children, Indiana University, Indianapolis, IN.

We performed a multicenter retrospective cohort study of children with 14 days to 18 years of age in the United States from 2011 to 2016 with cancer or hematopoietic cell transplant (HCT) who were supported with veno-venous extracorporeal membrane oxygenation (V-V ECMO). We compared the outcomes of children with oncological diagnoses or HCT supported with V-V ECMO to other children who have received V-V ECMO support. In this cohort of 204 patients supported with V-V ECMO, 30 (15%) had a diagnosis of cancer or a history of HCT. There were 21 patients who had oncological diagnoses without HCT and 9 children were post-HCT. The oncology/HCT group had a higher overall ICU mortality (67% vs. 28%, P < 0.001), mortality on ECMO (43% vs. 21%, P < 0.01), and ICU mortality among ECMO survivors (35% vs. 8%, P < 0.01). The oncology/HCT group had a higher rate of conversion to veno-arterial (V-A) ECMO (23% vs. 9%, P = 0.02) (RR, 2.5; 95% CI, 1.1-5.6). Children with cancer or HCT were older (6.6 vs. 2.9 years, P = 0.02) and had higher creatinine levels (0.65 vs. 0.4 mg/dL, P = 0.04) but were similar to the rest of the cohort for other pre-ECMO variables. For post-HCT patients, survival was significantly worse for those whose indication for HCT was cancer or immunodeficiency (0/6) as compared to other nonmalignant indications (3/3) (P = 0.01).
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http://dx.doi.org/10.1097/MAT.0000000000001336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328899PMC
August 2021

High-Frequency Jet Ventilation in Pediatric Acute Respiratory Failure.

Respir Care 2021 Feb 2;66(2):191-198. Epub 2020 Oct 2.

Division of Pediatric Critical Care Medicine, Duke Children's Hospital, Durham, North Carolina.

Background: High-frequency jet ventilation (HFJV) is primarily used in premature neonates; however, its use in pediatric patients with acute respiratory failure has been reported. The objective of this study was to evaluate HFJV use in the pediatric critical care setting. We hypothesized that HFJV would be associated with improvements in oxygenation and ventilation.

Methods: Medical records of all patients who received HFJV in the pediatric ICU of a quaternary care center between 2014 and 2018 were retrospectively reviewed. Premature infants who had not been discharged home were excluded, as were those in whom HFJV was started while on extracorporeal membrane oxygenation. Data on demographics, pulmonary mechanics, gas exchange, and outcomes were extracted and analyzed using chi-square testing for categorical variables, nonparametric testing for continuous variables, and a linear effects model to evaluate gas exchange over time.

Results: A total of 35 subjects (median age = 2.9 months, median weight = 5.2 kg) were included. Prior to HFJV initiation, median (interquartile range) oxygenation index (OI) was 11.3 (7.2-16.9), [Formula: see text] = 133 (91.3-190.0), pH = 7.18 (7.11-7.27), [Formula: see text] = 64 (52-87) mm Hg, and [Formula: see text] = 74 (64-125) mm Hg. For subjects still on HFJV ( = 25), there was no significant change in OI, [Formula: see text], or [Formula: see text] at 4-6 h after initiation, whereas pH increased ( = .001) and [Formula: see text] decreased ( = .001). For those remaining on HFJV for > 72 h ( = 12), the linear effects model revealed no differences over 72 h for OI, [Formula: see text], [Formula: see text], or mean airway pressure, but there was a decrease in [Formula: see text] while pH and [Formula: see text] increased. There were 9 (26%) subjects who did not survive, and nonsurvivors had higher Pediatric Index of Mortality 2 scores ( = .01), were more likely to be immunocompromised ( = .01), were less likely to have a documented infection ( = .02), and had lower airway resistance ( = .02).

Conclusions: HFJV was associated with improved ventilation among subjects able to remain on HFJV but had no significant effect on oxygenation.
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http://dx.doi.org/10.4187/respcare.08241DOI Listing
February 2021

Development of a novel intravascular oxygenator catheter: Oxygen mass transfer properties across nonporous hollow fiber membranes.

Biotechnol Bioeng 2021 01 7;118(1):345-356. Epub 2020 Oct 7.

Department of Civil & Environmental Engineering, Duke University, Durham, North Carolina, USA.

Despite hypoxic respiratory failure representing a large portion of total hospitalizations and healthcare spending worldwide, therapeutic options beyond mechanical ventilation are limited. We demonstrate the technical feasibility of providing oxygen to a bulk medium, such as blood, via diffusion across nonporous hollow fiber membranes (HFMs) using hyperbaric oxygen. The oxygen transfer across Teflon® membranes was characterized at oxygen pressures up to 2 bars in both a stirred tank vessel (CSTR) and a tubular device mimicking intravenous application. Fluxes over 550 ml min  m were observed in well-mixed systems, and just over 350 ml min  m in flow through tubular systems. Oxygen flux was proportional to the oxygen partial pressure inside the HFM over the tested range and increased with mixing of the bulk liquid. Some bubbles were observed at the higher pressures (1.9 bar) and when bulk liquid dissolved oxygen concentrations were high. High-frequency ultrasound was applied to detect and count individual bubbles, but no increase from background levels was detected during lower pressure operation. A conceptual model of the oxygen transport was developed and validated. Model parametric sensitivity studies demonstrated that diffusion through the thin fiber walls was a significant resistance to mass transfer, and that promoting convection around the fibers should enable physiologically relevant oxygen supply. This study indicates that a device is within reach that is capable of delivering greater than 10% of a patient's basal oxygen needs in a configuration that readily fits intravascularly.
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http://dx.doi.org/10.1002/bit.27574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920697PMC
January 2021

Extracorporeal Membrane Oxygenation for Hemodynamic Support.

Clin Perinatol 2020 09 26;47(3):671-684. Epub 2020 May 26.

Pediatric Critical Care Medicine, Duke Children's, Durham, NC, USA. Electronic address:

Extracorporeal membrane oxygenation was first successfully achieved in 1975 in a neonate with meconium aspiration. Neonatal extracorporeal membrane oxygenation has expanded to include hemodynamic support in cardiovascular collapse before and after cardiac surgery, medical heart disease, and rescue therapy for cardiac arrest. Advances in pump technology, circuit biocompatibility, and oxygenators efficiency have allowed extracorporeal membrane oxygenation to support neonates with increasingly complex pathophysiology. Contraindications include extreme prematurity, extremely low birth weight, lethal chromosomal abnormalities, uncontrollable hemorrhage, uncontrollable disseminated intravascular coagulopathy, and severe irreversible brain injury. The future will involve collaboration to guide and evolve evidence-based practices for this life-sustaining therapy.
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http://dx.doi.org/10.1016/j.clp.2020.05.016DOI Listing
September 2020

Dead Space to Tidal Volume Ratio Is Associated With Higher Postextubation Support in Children.

Respir Care 2020 Nov 30;65(11):1721-1729. Epub 2020 Jun 30.

Respiratory Care Services, Duke University Medical Center, Durham, North Carolina.

Background: Extubation failure is associated with increased duration of mechanical ventilation, length of hospital stay, and mortality. An elevated dead-space-to-tidal-volume ratio (V/V) has been proposed as a predictor of successful extubation in children. We hypothesized that a higher V/V value would be associated with extubation failure and higher postextubation respiratory support.

Methods: This was a prospective, observational, cohort study. All subjects were < 18 y old and were extubated in the pediatric multidisciplinary ICU or the cardiac ICU at an academic medical center from June 2016 through March 2017. Using arterial blood gas analysis and mainstream volumetric capnography, daily V/V measurements were obtained on intubated subjects using an automated algorithm. Respiratory support upon extubation was based on the clinical team's judgment and defined as low (ie, room air or nasal cannula) or high (ie, high-flow nasal cannula, CPAP, or bi-level positive airway pressure). Subjects were monitored for 48 h after extubation for escalation in respiratory support and need for re-intubation.

Results: Of 189 subjects included in the analysis, 166 were successfully extubated and 23 (12%) required re-intubation. There was no significant difference in final V/V between those who extubated successfully and those who failed extubation, with a median V/V of 0.28 (interquartile range [IQR] 0.20-0.37) vs 0.29 (IQR 0.21-0.33), respectively ( = .87). Those who received a high level of support upon extubation had a higher V/V than those who received a low level of support, with a median of 0.32 (IQR 0.23-0.39) vs 0.25 (IQR 0.16-0.30), respectively ( < .001). This association remained significant when controlling for age, duration of intubation, and cyanotic congenital heart disease (odds ratio 1.63, 95% CI 1.18-2.24).

Conclusions: There was no significant relationship between V/V and extubation success, although V/V was associated with the level of respiratory support provided following extubation. Further studies should investigate whether the use of V/V can help reduce extubation failure rates with varying levels of postextubation respiratory support.
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http://dx.doi.org/10.4187/respcare.07351DOI Listing
November 2020

Respiratory pathogens associated with intubated pediatric patients following hematopoietic cell transplant.

Transpl Infect Dis 2020 Aug 28;22(4):e13297. Epub 2020 Apr 28.

Division of Critical Care, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Background: We describe organisms found in the respiratory tracts of a multicenter cohort of pediatric hematopoietic cell transplant (HCT) recipients with respiratory failure.

Methods: Twelve centers contributed up to 25 pediatric allogeneic HCT recipients requiring mechanical ventilation for respiratory failure to a retrospective database. Positive respiratory pathogens and method of obtaining sample were recorded. Outcomes were assessed using Mann-Whitney U test or chi-squared analysis.

Results: Of the 222 patients in the database, ages 1 month through 21 years, 34.6% had a positive respiratory culture. 105 pathogens were identified in 77 patients; of those, 48.6% were viral, 34.3% bacterial, 16.2% fungal, and 1% parasitic. PICU mortality with a respiratory pathogen was 68.8% compared to 54.9% for those without a respiratory pathogen (P = .045). Those with a positive respiratory pathogen had longer PICU length of stay, 20 days (IQR 14.0, 36.8) vs 15 (IQR 6.5, 32.0), P = .002, and a longer course of mechanical ventilation, 17 days (IQR 10, 29.5) vs 8 (3, 17), P < .0001. Method of pathogen identification, type of pathogen, and the presence of multiple pathogens were not associated with changes in PICU outcomes.

Conclusions: In this multicenter retrospective cohort of intubated pediatric post-HCT patients, there was high variability in the respiratory pathogens identified. Type of pathogen and method of detection did not affect PICU mortality. The presence of any organism leads to increased PICU mortality, longer PICU stay, and increased duration of mechanical ventilation suggesting that early detection and treatment of pathogens may be beneficial in this population.
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http://dx.doi.org/10.1111/tid.13297DOI Listing
August 2020

High-frequency oscillatory ventilation for PARDS: awaiting PROSPect.

Crit Care 2020 03 27;24(1):118. Epub 2020 Mar 27.

Family and Community Health, School of Nursing, Anesthesia and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

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http://dx.doi.org/10.1186/s13054-020-2829-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099805PMC
March 2020

Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children.

Pediatr Crit Care Med 2020 02;21(2):e52-e106

Radboud University Medical Centre, Nijmegen, The Netherlands.

Objectives: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction.

Design: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process.

Methods: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate.

Results: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 52 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 49 research priorities were identified.

Conclusions: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.
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http://dx.doi.org/10.1097/PCC.0000000000002198DOI Listing
February 2020

Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.

Intensive Care Med 2020 02;46(Suppl 1):10-67

Radboud University Medical Centre, Nijmegen, The Netherlands.

Objectives: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction.

Design: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process.

Methods: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate.

Results: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 49 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 52 research priorities were identified.

Conclusions: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.
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http://dx.doi.org/10.1007/s00134-019-05878-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095013PMC
February 2020

Mechanical Ventilation in Children on Venovenous ECMO.

Respir Care 2020 Mar 28;65(3):271-280. Epub 2020 Jan 28.

Division of Pediatric Critical Care, Duke Children's Hospital and Health Center, Durham, North Carolina.

Background: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is used when mechanical ventilation can no longer support oxygenation or ventilation, or if the risk of ventilator-induced lung injury is considered excessive. The optimum mechanical ventilation strategy once on ECMO is unknown. We sought to describe the practice of mechanical ventilation in children on VV-ECMO and to determine whether mechanical ventilation practices are associated with clinical outcomes.

Methods: We conducted a multicenter retrospective cohort study in 10 pediatric academic centers in the United States. Children age 14 d through 18 y on VV-ECMO from 2011 to 2016 were included. Exclusion criteria were preexisting chronic respiratory failure, primary diagnosis of asthma, cyanotic heart disease, or ECMO as a bridge to lung transplant.

Results: Conventional mechanical ventilation was used in about 75% of children on VV-ECMO; the remaining subjects were managed with a variety of approaches. With the exception of PEEP, there was large variation in ventilator settings. Ventilator mode and pressure settings were not associated with survival. Mean ventilator F on days 1-3 was higher in nonsurvivors than in survivors (0.5 vs 0.4, = .009). In univariate analysis, other risk factors for mortality were female gender, higher Pediatric Risk Estimate Score for Children Using Extracorporeal Respiratory Support (Ped-RESCUERS), diagnosis of cancer or stem cell transplant, and number of days intubated prior to initiation of ECMO (all < .05). In multivariate analysis, ventilator F was significantly associated with mortality (odds ratio 1.38 for each 0.1 increase in F , 95% CI 1.09-1.75). Mortality was higher in subjects on high ventilator F (≥ 0.5) compared to low ventilator F (> 0.5) (46% vs 22%, = .001).

Conclusions: Ventilator mode and some settings vary in practice. The only ventilator setting associated with mortality was F , even after adjustment for disease severity. Ventilator F is a modifiable setting that may contribute to mortality in children on VV-ECMO.
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http://dx.doi.org/10.4187/respcare.07214DOI Listing
March 2020

Components of Risk and Modifiable Factors in Chronically Mechanically Ventilated Patients: Have We Fully Defined Them?

Respir Care 2019 12;64(12):1598-1599

Pediatrics and Anesthesiology Duke Children's Hospital Durham, North Carolina.

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http://dx.doi.org/10.4187/respcare.07512DOI Listing
December 2019

Clinical trials and future directions in pediatric acute respiratory distress syndrome.

Ann Transl Med 2019 Oct;7(19):514

Section Chief Pediatric Cardiac ICU, Duke Children's Hospital, Duke University Medical Center, Durham, NC, USA.

The pediatric acute respiratory distress syndrome (PARDS), a description specific for children with acute respiratory distress syndrome (ARDS), was proposed in the recent Pediatric Acute Lung Injury Consensus Conference (PALICC, 2015). This recent standardization of PARDS diagnosis is expected to aid in uniform earlier recognition of the entity, enable use of consistent management strategies and potentially increase the ease of enrollment in future PARDS clinical trials-all of which are expected to optimize outcomes in PARDS. Clinical trials in PARDS are few but ongoing studies are expected to lay the foundation for future clinical studies. The Randomized Evaluation of Sedation Titration for Respiratory Failure trial (RESTORE) trial has revealed that a goal directed sedation protocol does not reduce the duration of invasive ventilation in critically ill children. PROSpect trial is a large multi-institute clinical trial that is expected to reveal optimal ventilation strategies and patient positioning (supine prone) in patients with severe PARDS. The PARDS neuromuscular blockade (NMB) study is expected to yield important information about the impact of active NMB on PARDS outcomes. Information from these studies could be used to design future clinical trials in PARDS and to lessen the anecdotal or extrapolated experiences from adult clinical studies that often guide clinical practices in PARDS management. Finally, it is expected that these definitions and management strategies will be revised periodically as our understanding of PARDS evolves. Emerging data on PARDS subtypes suggest that patient heterogeneity is an important factor in designing these clinical trials.
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http://dx.doi.org/10.21037/atm.2019.09.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828784PMC
October 2019

Correlation between Regional Cerebral Saturation and Invasive Cardiac Index Monitoring after Heart Transplantation Surgery.

J Pediatr Intensive Care 2018 Dec 11;7(4):196-200. Epub 2018 Jun 11.

Division of Pediatric Critical Care, Department of Pediatrics, Kravis Children's Hospital at Mount Sinai, New York, United States.

The present study assessed the correlations between cerebral regional saturation detected by near infrared spectroscopy (NIRS) and cardiac index (CI) measured by pulmonary artery catheter. This was a retrospective cohort study conducted in the cardiac intensive care unit in a tertiary care children's hospital. Patients younger than 18 years of age who underwent heart transplantation and had a pulmonary artery catheter on admission to the pediatric cardiac intensive care unit between January, 2010, and August, 2013, were included. There were no interventions. A total of 10 patients were included with median age of 14 years (range, 7-17). Indications for transplantation were dilated cardiomyopathy (  = 9) and restrictive cardiomyopathy (  = 1). Mixed venous oxygen saturation (SvO ), cerebral regional tissue saturation (rSO ), and CI were recorded hourly for 8 to 92 hours post-transplantation. Spearman's rank correlation coefficient was used to assess correlations between SvO and cerebral rSO and between CI and cerebral rSO . A total of 410 data points were collected. Median, 25th and 75th percentiles of cerebral rSO , CI, and SvO were 65% (54-69), 2.9 L/min/m (2.2-4.0), and 75% (69-79), respectively. The correlation coefficient between cerebral rSO and CI was 0.104 (  = 0.034) and that for cerebral rSO and SvO was 0.11 (  = 0.029). The correlations between cerebral rSO and CI and between cerebral rSO and SvO were weak. Cerebral rSO as detected by NIRS may not be an accurate indicator of CI in critically ill patients.
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http://dx.doi.org/10.1055/s-0038-1660788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506669PMC
December 2018

Emerging approaches in pediatric mechanical ventilation.

Expert Rev Respir Med 2019 04;13(4):327-336

b Division of Pediatric Critical Care Medicine, Department of Pediatrics , Duke Children's Hospital , Durham , NC , USA.

Introduction: The use of mechanical ventilation is an invaluable tool in caring for critically ill patients. Enhancing our capabilities in mechanical ventilation has been instrumental in the ability to support clinical conditions and diseases which were once associated with high mortality. Areas covered: Within this manuscript, we will look to discuss emerging approaches to improving the care of pediatric patients who require mechanical ventilation. After an extensive literature search, we will provide a brief review of the history and pathophysiology of acute respiratory distress syndrome, an assessment of several ventilator settings, a discussion on assisted ventilation, review of therapy used to rescue in severe respiratory failure, methods of monitoring the effects of mechanical ventilation, and nutrition. Expert opinion: As we have advanced in our care, we are seeing children survive illnesses that would have once claimed their lives. Given this knowledge, we must continue to advance the research in pediatric critical care to understand the means in which we can tailor the therapy to the patient in efforts to efficiently liberate them from mechanical ventilation once their illness has resolved.
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http://dx.doi.org/10.1080/17476348.2019.1586536DOI Listing
April 2019

Feasibility of an alternative, physiologic, individualized open-lung approach to high-frequency oscillatory ventilation in children.

Ann Intensive Care 2019 Jan 18;9(1). Epub 2019 Jan 18.

Department of Paediatrics, Division of Paediatric Critical Care Medicine, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Huispost CA 80, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.

Background: High-frequency oscillatory ventilation (HFOV) is a common but unproven management strategy in paediatric critical care. Oscillator settings have been traditionally guided by patient age and/or weight rather than by lung mechanics, thereby potentially negating any beneficial effects. We have adopted an open-lung HFOV strategy based on a corner frequency approach using an initial incremental-decremental mean airway pressure titration manoeuvre, a high frequency (8-15 Hz), and high power to initially target a proximal pressure amplitude (∆P) of 70-90 cm HO, irrespective of age or weight.

Methods: We reviewed prospectively collected data on patients < 18 years of age who were managed with HFOV for acute respiratory failure. We measured metrics for oxygenation, ventilation, and haemodynamics as well as the use of sedative-analgesic medications and neuromuscular blocking agents.

Results: Data from 115 non-cardiac patients were analysed, of whom 53 had moderate-to-severe paediatric acute respiratory distress syndrome (PARDS). Sixteen patients (13.9%) died. Frequencies≥ 8 Hz and high ∆P were achieved in all patients irrespective of age or PARDS severity. Patients with severe PARDS showed the greatest improvement in oxygenation. pH and PaCO normalized in all patients. Haemodynamic parameters, cumulative amount of fluid challenges, and daily fluid balance did not deteriorate after transitioning to HFOV in any age or PARDS severity group. We observed a transient increase neuromuscular blocking agent use after switching to HFOV, but there was no increase in the daily cumulative amount of continuous midazolam or morphine in any age or PARDS severity group. No patients experienced clinically apparent barotrauma.

Conclusions: This is the first study reporting the feasibility of an alternative, individualized, physiology-based open-lung HFOV strategy targeting high F and high ∆P. No adverse effects were observed with this strategy. Our findings warrant further systematic evaluation.
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http://dx.doi.org/10.1186/s13613-019-0492-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338613PMC
January 2019

Spontaneous Breathing in Acute Respiratory Distress Syndrome: Remains an Unanswered Question.

Authors:
Ira M Cheifetz

Crit Care Med 2019 02;47(2):297-298

Division of Pediatric Critical Care Medicine, Duke Children's Hospital, Durham, NC.

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http://dx.doi.org/10.1097/CCM.0000000000003563DOI Listing
February 2019

Optoacoustic Evaluation of Endotracheal Tube Depth in Pediatrics.

Respir Care 2018 12;63(12):1575-1576

Duke University Medical Center Durham, North Carolina.

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http://dx.doi.org/10.4187/respcare.06687DOI Listing
December 2018

Consensus Recommendations for RBC Transfusion Practice in Critically Ill Children From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative.

Pediatr Crit Care Med 2018 09;19(9):884-898

Department of Pediatrics and Pathology, George Washington University, Washington, DC.

Objectives: To date, there are no published guidelines to direct RBC transfusion decision-making specifically for critically ill children. We present the recommendations from the Pediatric Critical Care Transfusion and Anemia Expertise Initiative.

Design: Consensus conference series of multidisciplinary, international experts in RBC transfusion management of critically ill children.

Setting: Not applicable.

Intervention: None.

Subjects: Children with, or children at risk for, critical illness who receive or are at risk for receiving a RBC transfusion.

Methods: A panel of 38 content and four methodology experts met over the course of 2 years to develop evidence-based, and when evidence lacking, expert consensus-based recommendations regarding decision-making for RBC transfusion management and research priorities for transfusion in critically ill children. The experts focused on nine specific populations of critically ill children: general, respiratory failure, nonhemorrhagic shock, nonlife-threatening bleeding or hemorrhagic shock, acute brain injury, acquired/congenital heart disease, sickle cell/oncology/transplant, extracorporeal membrane oxygenation/ventricular assist/ renal replacement support, and alternative processing. Data to formulate evidence-based and expert consensus recommendations were selected based on searches of PubMed, EMBASE, and Cochrane Library from 1980 to May 2017. Agreement was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method.

Measurements And Results: The Transfusion and Anemia Expertise Initiative consensus conference developed and reached consensus on a total of 102 recommendations (57 clinical [20 evidence based, 37 expert consensus], 45 research recommendations). All final recommendations met agreement, defined a priori as greater than 80%. A decision tree to aid clinicians was created based on the clinical recommendations.

Conclusions: The Transfusion and Anemia Expertise Initiative recommendations provide important clinical guidance and applicable tools to avoid unnecessary RBC transfusions. Research recommendations identify areas of focus for future investigation to improve outcomes and safety for RBC transfusion.
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http://dx.doi.org/10.1097/PCC.0000000000001613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126913PMC
September 2018

Recommendations on the Indications for RBC Transfusion for the Critically Ill Child Receiving Support From Extracorporeal Membrane Oxygenation, Ventricular Assist, and Renal Replacement Therapy Devices From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative.

Pediatr Crit Care Med 2018 09;19(9S Suppl 1):S157-S162

Department of Pediatrics, University of Minnesota, Minneapolis, MN.

Objectives: To present recommendations and supporting literature for RBC transfusions in critically ill children supported with extracorporeal membrane oxygenation, ventricular assist devices, or renal replacement therapy.

Design: Consensus conference series of international, multidisciplinary experts in RBC transfusion management of critically ill children.

Methods: The panel of 38 experts developed evidence-based, and when evidence was lacking, expert-based clinical recommendations as well as research priorities for RBC transfusions in critically ill children. The extracorporeal membrane oxygenation/ventricular assist device/renal replacement therapy subgroup included six experts. We conducted electronic searches of the PubMed, EMBASE, and Cochrane Library databases from 1980 to May 2017, using medical subject heading terms and text words to define concepts of RBC transfusion, extracorporeal membrane oxygenation, ventricular assist device, and renal replacement therapy. We used a standardized data extraction form to construct evidence tables and graded the evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Recommendations developed and supporting literature were reviewed and scored by all panel members. Agreement was obtained using the Research and Development/UCLA Appropriateness Method.

Results: For inpatients requiring extracorporeal membrane oxygenation, ventricular assist device, or renal replacement therapy support, there was expert agreement (> 80%) on five good practice statements aimed to improve accuracy and uniform reporting of RBC transfusion data in pediatric extracorporeal membrane oxygenation, ventricular assist device, and renal replacement therapy studies and quality improvement projects; four clinical recommendations of physiologic metrics and biomarkers of oxygen delivery, in addition to hemoglobin concentration, to guide RBC transfusion, acknowledging insufficient evidence to recommend specific RBC transfusion strategies; and eight research recommendations.

Conclusions: Further research surrounding indications, risks, benefits, and alternatives to RBC transfusion in children on extracorporeal devices is clearly needed. Using a structured literature review and grading process, the Transfusion and Anemia Expertise Initiative panel concluded that there is currently insufficient evidence to recommend specific RBC transfusion variables in children requiring extracorporeal membrane oxygenation, ventricular assist device, or renal replacement therapy support.
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http://dx.doi.org/10.1097/PCC.0000000000001600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125786PMC
September 2018

Correlation between minute carbon dioxide elimination and pulmonary blood flow in single-ventricle patients after stage 1 palliation and 2-ventricle patients with intracardiac shunts: A pilot study.

Paediatr Anaesth 2018 07;28(7):618-624

Division of Pediatric Critical Care, Department of Pediatrics, Kravis Children's Hospital at Mount Sinai, New York, NY, USA.

Background: Assessment of pulmonary blood flow and cardiac output is critical in the postoperative management of patients with single-ventricle physiology or 2-ventricle physiology with intracardiac shunting. Currently, such hemodynamic data are only obtainable by invasive procedures, such as cardiac catheterization or the use of a pulmonary artery catheter. Ready availability of such information, especially if attainable noninvasively, could be a valuable addition to postoperative management.

Aims: The aim of this study was to assess the correlation between volume of CO elimination obtained by volumetric capnography and pulmonary blood flow in pediatric patients with single-ventricle physiology after stage 1 palliation as well as in patients with other cardiac lesions associated with intracardiac shunting.

Methods: This prospective cohort study included children with congenital or acquired heart disease who underwent cardiac catheterization as part of clinical care. Cardiac output, pulmonary blood flow, and volume of CO elimination were simultaneously collected. Spearman's rank correlation coefficients were used to assess correlation between measurements after controlling for minute ventilation.

Results: Thirty-five patients were enrolled and divided into 3 groups. Group 1 (n = 8) included single-ventricle patients after stage 1 palliation. Group 2 (n = 10) patients had structural heart disease with 2 ventricles and intracardiac shunting. Group 3 (n = 17) had structurally normal hearts. Among Group 1 patients, the correlation coefficients (R ) between volume of CO elimination and pulmonary blood flow and volume of CO elimination and cardiac output were 0.60 (P = .02) 95% CI [0.01-0.79] and 0.29 (P = .74) 95% CI [-0.91 - 0.86], respectively. In patients with 2 ventricles associated with intracardiac shunts (Group 2), the correlation coefficients between volume of CO elimination and pulmonary blood flow and volume of CO elimination and cardiac output were 0.86 (P = .001) 95% CI [0.53 - 0.97] and 0.73 (P = .001) 95% CI [0.29 - 0.95], respectively. Among Group 3 patients, the correlation coefficient between volume of CO elimination and pulmonary blood flow was 0.66 (P = .038) 95% CI [0.29 - 0.87].

Conclusion: Volume of CO elimination may be a surrogate marker of pulmonary blood flow in single-ventricle patients and patients with biventricular physiology with intracardiac shunting. Also, among patients with normal cardiac anatomy, volume of CO elimination may be a marker of cardiac output.
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http://dx.doi.org/10.1111/pan.13423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485938PMC
July 2018

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy.

Nat Rev Clin Oncol 2019 01;16(1):45-63

Department of Pediatrics, Blood and Marrow Transplantation Program, Keck School of Medicine, University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, USA.

In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19 acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care. Herein, authors representing the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Stem Cell Transplantation (HSCT) Subgroup and the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program have collaborated to provide comprehensive consensus guidelines on the care of children receiving CAR T cell therapy.
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http://dx.doi.org/10.1038/s41571-018-0075-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096894PMC
January 2019
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