Publications by authors named "Anil Sapru"

74 Publications

The Pulmonary Metatranscriptome Prior to Pediatric Hematopoietic Cell Transplantation Identifies Post-HCT Lung Injury.

Blood 2020 Dec 23. Epub 2020 Dec 23.

Chan Zuckerberg Biohub, United States.

Lung injury after pediatric allogeneic hematopoietic cell transplantation (HCT) is a common and disastrous complication that threatens long-term survival. In order to develop strategies to prevent lung injury, novel tools are first needed to comprehensively assess lung health in HCT candidates. Therefore, this study analyzed biospecimens from 181 pediatric HCT candidates who underwent routine pre-HCT bronchoalveolar lavage (BAL) at the University Medical Center in Utrecht, the Netherlands between 2005-2016. BAL fluid underwent metatranscriptomic sequencing of microbial and human RNA and unsupervised clustering and generalized linear models were used to associate microbiome-gene expression data with the development of post-HCT lung injury. Microbe-gene correlations were validated using a geographically distinct cohort of 18 pediatric HCT candidates. The cumulative incidence of post-HCT lung injury varied significantly according to four pre-HCT pulmonary metatranscriptome clusters, with the highest incidence observed in children with pre-HCT viral enrichment and innate immune activation and in children with profound microbial depletion and concomitant NK/T-cell activation (p<0.001). In contrast, children with pre-HCT pulmonary metatranscriptomes containing diverse oropharyngeal taxa and lacking inflammation rarely developed post-HCT lung injury. In addition, activation of epithelial-epidermal differentiation, mucous production, and cellular adhesion were associated with fatal post-HCT lung injury. In a separate validation cohort, associations between pulmonary respiratory viral load, oropharyngeal taxa, and pulmonary gene expression were recapitulated; the association with post-HCT lung injury needs to be validated in an independent cohort. This analysis suggests that assessment of the pre-HCT BAL fluid may identify high-risk pediatric HCT candidates who may benefit from pathobiology-targeted interventions.
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http://dx.doi.org/10.1182/blood.2020009246DOI Listing
December 2020

Hemostatic Balance in Pediatric Acute Liver Failure: Epidemiology of Bleeding and Thrombosis, Physiology, and Current Strategies.

Front Pediatr 2020 23;8:618119. Epub 2020 Dec 23.

Division of Pediatric Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Pediatric Acute Liver Failure (PALF) is a rapidly progressive clinical syndrome encountered in the pediatric ICU which may rapidly progress to multi-organ dysfunction, and on occasion to life threatening cerebral edema and hemorrhage. Pediatric Acute Liver Failure is defined as severe acute hepatic dysfunction accompanied by encephalopathy and liver-based coagulopathy defined as prolongation of International Normalized Ratio (INR) >1.5. However, coagulopathy in PALF is complex and warrants a deeper understanding of the hemostatic balance in acute liver failure. Although an INR value of >1.5 is accepted as the evidence of coagulopathy and has historically been viewed as a prognostic factor of PALF, it may not accurately reflect the bleeding risk in PALF since it only measures procoagulant factors. Paradoxically, despite the prolongation of INR, bleeding risk is lower than expected (around 5%). This is due to "rebalanced hemostasis" due to concurrent changes in procoagulant, anticoagulant and fibrinolytic systems. Since the liver is involved in both procoagulant (Factors II, V, IX, XI, and fibrinogen) and anticoagulant (Protein C, Protein S, and antithrombin) protein synthesis, PALF results in "rebalanced hemostasis" or even may shift toward a hypercoagulable state. In addition to rebalanced coagulation there is altered platelet production due to decreased thrombopoietin production by liver, increased von Willebrand factor from low grade endothelial cell activation, and hyperfibrinolysis and dysfibrinogenemia from altered synthetic liver dysfunction. All these alterations contribute to the multifactorial nature of coagulopathy in PALF. Over exuberant use of prophylactic blood products in patients with PALF may contribute to morbidities such as fluid overload, transfusion-associated lung injury, and increased thrombosis risk. It is essential to use caution when using INR values for plasma and factor administration. In this review we will summarize the complexity of coagulation in PALF, explore "rebalanced hemostasis," and discuss the limitations of current coagulation tests. We will also review strategies to accurately diagnose the coagulopathy of PALF and targeted therapies.
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http://dx.doi.org/10.3389/fped.2020.618119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786276PMC
December 2020

Obesity and smoking as risk factors for invasive mechanical ventilation in COVID-19: A retrospective, observational cohort study.

PLoS One 2020 22;15(12):e0238552. Epub 2020 Dec 22.

Division of Pulmonary and Critical Care, Department of Medicine, UCLA Medical Center, Los Angeles, CA, United States of America.

Purpose: To describe the trajectory of respiratory failure in COVID-19 and explore factors associated with risk of invasive mechanical ventilation (IMV).

Materials And Methods: A retrospective, observational cohort study of 112 inpatient adults diagnosed with COVID-19 between March 12 and April 16, 2020. Data were manually extracted from electronic medical records. Multivariable and Univariable regression were used to evaluate association between baseline characteristics, initial serum markers and the outcome of IMV.

Results: Our cohort had median age of 61 (IQR 45-74) and was 66% male. In-hospital mortality was 6% (7/112). ICU mortality was 12.8% (6/47), and 18% (5/28) for those requiring IMV. Obesity (OR 5.82, CI 1.74-19.48), former (OR 8.06, CI 1.51-43.06) and current smoking status (OR 10.33, CI 1.43-74.67) were associated with IMV after adjusting for age, sex, and high prevalence comorbidities by multivariable analysis. Initial absolute lymphocyte count (OR 0.33, CI 0.11-0.96), procalcitonin (OR 1.27, CI 1.02-1.57), IL-6 (OR 1.17, CI 1.03-1.33), ferritin (OR 1.05, CI 1.005-1.11), LDH (OR 1.57, 95% CI 1.13-2.17) and CRP (OR 1.13, CI 1.06-1.21), were associated with IMV by univariate analysis.

Conclusions: Obesity, smoking history, and elevated inflammatory markers were associated with increased need for IMV in patients with COVID-19.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238552PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755188PMC
January 2021

A Core Outcome Set for Pediatric Critical Care.

Crit Care Med 2020 Dec;48(12):1819-1828

1Department of Critical Care Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA. 2Department of Pediatrics, Critical Care Medicine, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO. 3Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA. 4Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT. 5Department of Molecular Biology, Princeton University, Princeton, NJ. 6Department of Pediatrics, Children's National Hospital, Washington, DC. 7Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI. 8Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH. 9Department of Pediatrics, Mattel Children's Hospital, University of California Los Angeles, Los Angeles, CA. 10Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA. 11Collaborative Pediatric Critical Care Research Network Family Collaborative, Great Falls, VA. 12Department of Paediatrics and Child Health, University of Cape Town, and Red Cross War Memorial Children's Hospital, Cape Town, South Africa. 13Department of Pediatrics, University of São Paulo, São Paulo, Brazil. 14Intensive Care Department of Paediatrics, The Royal Childrens Hospital, Melbourne, VIC, Australia. 15Departments of Pediatrics and Critical Care, McMaster University, Hamilton, ON, Canada. 16Department of Family and Community Health (Nursing), Anesthesiology and Critical Care (Perelman School of Medicine), University of Pennsylvania; Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA. 17Department of Pediatric Critical Care, Hospital de Niños Dr R. Gutierrez, Buenos Aires, Argentina. 18Department of Pediatric Intensive Care, Istanbul University, Child Health Institute and Istanbul Faculty of Medicine, Istanbul, Turkey. 19Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA. 20Department of Paediatrics, Centrum Universiteit van Amsterdam, Amsterdam, The Netherlands. 21Department of Pediatric Subspecialities, KK Women's and Children's Hospital, Singapore. 22School of Nursing, Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, QLD, Australia. 23Children and Young People Health Research, School of Health Sciences, University of Nottingham and Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom. 24Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa. 25Department of Pediatrics, All India Institute of Medical Sciences, Chandigarh, India. 26Department of Neuropsychology, Kennedy Krieger Institute and Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD. 27Department of Pediatrics, University of Washington School of Medicine and Center for Child Health, Behavior, and Development, Seattle Children's Research Institute, Seattle, WA.

Objectives: More children are surviving critical illness but are at risk of residual or new health conditions. An evidence-informed and stakeholder-recommended core outcome set is lacking for pediatric critical care outcomes. Our objective was to create a multinational, multistakeholder-recommended pediatric critical care core outcome set for inclusion in clinical and research programs.

Design: A two-round modified Delphi electronic survey was conducted with 333 invited research, clinical, and family/advocate stakeholders. Stakeholders completing the first round were invited to participate in the second. Outcomes scoring greater than 69% "critical" and less than 15% "not important" advanced to round 2 with write-in outcomes considered. The Steering Committee held a virtual consensus conference to determine the final components.

Setting: Multinational survey.

Patients: Stakeholder participants from six continents representing clinicians, researchers, and family/advocates.

Measurements And Main Results: Overall response rates were 75% and 82% for each round. Participants voted on seven Global Domains and 45 Specific Outcomes in round 1, and six Global Domains and 30 Specific Outcomes in round 2. Using overall (three stakeholder groups combined) results, consensus was defined as outcomes scoring greater than 90% "critical" and less than 15% "not important" and were included in the final PICU core outcome set: four Global Domains (Cognitive, Emotional, Physical, and Overall Health) and four Specific Outcomes (Child Health-Related Quality of Life, Pain, Survival, and Communication). Families (n = 21) suggested additional critically important outcomes that did not meet consensus, which were included in the PICU core outcome set-extended.

Conclusions: The PICU core outcome set and PICU core outcome set-extended are multistakeholder-recommended resources for clinical and research programs that seek to improve outcomes for children with critical illness and their families.
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http://dx.doi.org/10.1097/CCM.0000000000004660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785252PMC
December 2020

Therapeutic Alliance Between Bereaved Parents and Physicians in the PICU.

Pediatr Crit Care Med 2020 Oct 9. Epub 2020 Oct 9.

Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI.

Objectives: Therapeutic alliance is the collaborative bond that develops between patients/families and healthcare providers. Our objective is to determine the extent of therapeutic alliance bereaved parents perceive to have occurred with their child's physicians during their child's PICU stay, and associated factors.

Design: Multicenter observational study.

Setting: Eight children's hospitals affiliated with the Collaborative Pediatric Critical Care Research Network.

Patients: Parents greater than or equal to 18 years old whose child died in a PICU (including cardiac ICU).

Interventions: Bereaved parents completed the Human Connection Scale, a 16-item measure of therapeutic alliance, 6 months after their child's death. Human Connection Scale scores range from 16 to 64 with higher scores indicating greater alliance. Parents provided sociodemographic data, and medical records were reviewed for the child's clinical characteristics.

Measurements And Main Results: Two-hundred and thirty-three parents of 157 deceased children responded to the Human Connection Scale with greater than or equal to 80% item completion. Among parents, 146 (62.7%) were female, 155 (66.5%) were White and 46 (19.7%) were Black, 175 (75.1%) were married, and 209 (89.7%) had at least a high-school education. Among children, median age at the time of death was 5.9 years (interquartile range, 0.64-13.9 yr) and 114 (72.6%) died after limitation or withdrawal of life support. Mean Human Connection Scale score was 51.4 ± 11.1 for all parents, 52.6 ± 9.0 for White parents, and 47.0 ± 13.7 for Black parents. In multivariable modeling predicting Human Connection Scale scores, race was the only parent or child characteristic in the final model. Human Connection Scale scores were significantly different (-4.56; 95% CI, -8.53 to -0.6; p = 0.025) between the Black and White parents with items about trust, care, and honest communication showing the greatest mean difference.

Conclusions: Among parents bereaved in the PICU, therapeutic alliance with physicians is moderately high. Future research should identify strategies to strengthen therapeutic alliance with Black parents and examine the role of alliance on bereaved parents' health outcomes.
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http://dx.doi.org/10.1097/PCC.0000000000002585DOI Listing
October 2020

Temporal airway microbiome changes related to ventilator associated pneumonia in children.

Eur Respir J 2020 Oct 2. Epub 2020 Oct 2.

Biostatistics and Informatics, University of Colorado, Colorado School of Public Health, Aurora, CO, USA.

We sought to determine whether temporal changes in the lower airway microbiome are associated with ventilator-associated pneumonia (VAP) in children.Using a multicenter prospective study of children 31 days to 18 years requiring mechanical ventilation (MV) support for >72 h, daily tracheal aspirates were collected and analysed by sequencing of the 16S rRNA gene. VAP was assessed using 2008 CDC pediatric criteria. The association between microbial factors and VAP was evaluated using joint longitudinal time-to-event modelling, matched case-control comparisons, and unsupervised clustering.Of 366 eligible subjects, 66 (15%) developed VAP at a median of 5 (IQR: 3-5) days post intubation. At intubation, there was no difference in total bacterial load (TBL), but Shannon diversity and the relative abundance of and were lower for VAP subjects non-VAP subjects. However, higher TBL on each sequential day was associated with a lower hazard (HR: 0.39; CI: 0.23, 0.64) for developing VAP, but sequential values of diversity were not associated with VAP. Similar findings were observed from the matched analysis and unsupervised clustering. The most common dominant VAP pathogens included species (19%), (14%), and (10%). and were also identified as dominant organisms in several subjects.In mechanically ventilated children, changes over time in microbial factors were marginally associated with VAP risk, although these changes were not suitable for predicting VAP in individual patients. These findings suggest that focusing exclusively on pathogen burden may not adequately inform VAP diagnosis.
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http://dx.doi.org/10.1183/13993003.01829-2020DOI Listing
October 2020

Obesity and Smoking as Risk Factors for Invasive Mechanical Ventilation in COVID-19: a Retrospective, Observational Cohort Study.

medRxiv 2020 Aug 14. Epub 2020 Aug 14.

Division of Pulmonary and Critical Care, UCLA Medical Center.

Purpose: To describe the trajectory of respiratory failure in COVID-19 and explore factors associated with risk of invasive mechanical ventilation (IMV).

Materials And Methods: A retrospective, observational cohort study of 112 inpatient adults diagnosed with COVID-19 between March 12 and April 16, 2020. Data were manually extracted from electronic medical records. Multivariable and Univariable regression were used to evaluate association between baseline characteristics, initial serum markers and the outcome of IMV.

Results: Our cohort had median age of 61 (IQR 45-74) and was 66% male. In-hospital mortality was 6% (7/112). ICU mortality was 12.8% (6/47), and 18% (5/28) for those requiring IMV. Obesity (OR 5.82, CI 1.74-19.48), former (OR 8.06, CI 1.51-43.06) and current smoking status (OR 10.33, CI 1.43-74.67) were associated with IMV after adjusting for age, sex, and high prevalence comorbidities by multivariable analysis. Initial absolute lymphocyte count (OR 0.33, CI 0.11-0.96), procalcitonin (OR 1.27, CI 1.02-1.57), IL-6 (OR 1.17, CI 1.03-1.33), ferritin (OR 1.05, CI 1.005-1.11), LDH (OR 1.57, 95% CI 1.13-2.17) and CRP (OR 1.13, CI 1.06-1.21), were associated with IMV by univariate analysis.

Conclusions: Obesity, smoking history, and elevated inflammatory markers were associated with increased need for IMV in patients with COVID-19.
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http://dx.doi.org/10.1101/2020.08.12.20173849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430603PMC
August 2020

Acute Kidney Injury and Outcomes in Children Undergoing Noncardiac Surgery: A Propensity-Matched Analysis.

Anesth Analg 2021 02;132(2):332-340

From the Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California.

Background: Acute kidney injury (AKI) has been well documented in adults after noncardiac surgery and demonstrated to be associated with adverse outcomes. We report the prevalence of AKI after pediatric noncardiac surgery, the perioperative factors associated with postoperative AKI, and the association of AKI with postoperative outcomes in children undergoing noncardiac surgery.

Methods: Patients ≤18 years of age who underwent noncardiac surgery with serum creatinine during the 12 months preceding surgery and no history of end-stage renal disease were included in this retrospective observational study at a single tertiary academic hospital. Patients were evaluated during the first 7 days after surgery for development of any stage of AKI, according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Patients were classified into stages of KDIGO AKI for the purposes of describing prevalence. For further analyses, patients were grouped into those who developed any stage of AKI postoperatively and those who did not. Additionally, the time point at which each patient was first diagnosed with stage I AKI or greater was also assessed. Pre-, intra-, and postoperative factors were compared between the 2 groups. A multivariable Cox proportional hazards regression model was created to examine the time to first diagnosis of AKI using all nonredundant covariates. Analysis of the association of AKI with postoperative outcomes, mortality and 30-day readmission, was undertaken utilizing propensity score-matched controls and a multivariable Cox proportional hazards regression model.

Results: A total of 25,203 cases between 2013 and 2018 occurred; 8924 met inclusion criteria. Among this cohort, the observed prevalence of postoperative AKI was 3.2% (288 cases; confidence interval [CI], 2.9-3.6). The multivariable Cox model showed American Society of Anesthesiologists (ASA) status to be associated with the development of postoperative AKI. Several other factors, including intraoperative hypotension, were significantly associated with postoperative AKI in univariable models but found not to be significantly associated after adjustment. The multivariable Cox analyses with propensity-matched controls showed an estimated hazard ratio of 3.28 for mortality (CI, 1.71-6.32, P < .001) and 1.55 for 30-day readmission (CI, 1.08-2.23, P = .018) in children who developed AKI versus those who did not.

Conclusions: In children undergoing noncardiac surgery, postoperative AKI occurred in 3.2% of patients. Several factors, including intraoperative hypotension, were significantly associated with postoperative AKI in univariable models. After adjustment, only ASA status was found to be significantly associated with AKI in children after noncardiac surgery. Postoperative AKI was found to be associated with significantly higher rates of mortality and 30-day readmission in multivariable, time-varying models with propensity-matched controls.
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http://dx.doi.org/10.1213/ANE.0000000000005069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855789PMC
February 2021

Association of patient weight status with plasma surfactant protein D, a biomarker of alveolar epithelial injury, in children with acute respiratory failure.

Pediatr Pulmonol 2020 10 7;55(10):2730-2736. Epub 2020 Aug 7.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.

Aims And Objectives: Alveolar epithelial injury is a key determinant of acute respiratory failure (ARF) severity. Plasma surfactant protein D (SP-D), a biomarker of alveolar epithelial injury, is lower in obese adults with ARF compared to their lean peers. We aimed to determine if children with ARF have similar variance in plasma SP-D associated with their weight status on admission.

Methods: Plasma SP-D was measured on days 0, 1, or 2 in children (1-18 years) with ARF enrolled in the genetic variation and biomarkers in children with acute lung injury and RESTORE studies. Weight classification (underweight, normal, overweight, and obese) was based on body mass index or weight-for-height z-scores. Associations between weight group and SP-D on each day were tested.

Results: Inclusion criteria were met in 212 subjects, 24% were obese. There were no differences among weight groups in SP-D levels on days 0 and 1. However, on day 2, there was a statistically significant linear trend for lower SP-D levels as weight increased in both the univariate analysis (P = .02) and when adjusting for age, ethnicity, and diagnosis of pediatric acute respiratory distress syndrome (P = .05).

Conclusions: Obesity was associated with lower plasma SP-D levels on day 2 of ARF. This finding may be explained by altered ARF pathogenesis in obese individuals or a reduced incidence of ventilator-induced lung injury.
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http://dx.doi.org/10.1002/ppul.24990DOI Listing
October 2020

Trajectories and Risk Factors for Altered Physical and Psychosocial Health-Related Quality of Life After Pediatric Community-Acquired Septic Shock.

Pediatr Crit Care Med 2020 10;21(10):869-878

Department of Pediatrics, Seattle Children's Hospital, Seattle Research Institute, University of Washington School of Medicine, Seattle, WA.

Objectives: To evaluate the physical and psychosocial domains of health-related quality of life among children during the first year following community-acquired septic shock, and explore factors associated with poor physical and psychosocial health-related quality of life outcomes.

Design: Secondary analysis of the Life After Pediatric Sepsis Evaluation.

Setting: Twelve academic PICUs in the United States.

Patients: Children greater than or equal to 1 month and less than 18 years old who were perceived to be without severe developmental disability by their family caregiver at baseline and who survived hospitalization for community-acquired septic shock.

Interventions: Family caregivers completed the Pediatric Quality of Life Inventory for children 2-18 years old or the Pediatric Quality of Life Inventory Infant Scales for children less than 2 years old at baseline (reflecting preadmission status), day 7, and months 1, 3, 6, and 12 following PICU admission. Higher Pediatric Quality of Life Inventory Physical and Psychosocial Health Summary Scores indicate better health-related quality of life.

Measurements And Main Results: Of 204 children, 58 (28.2%) had a complex chronic comorbid condition. Children with complex chronic comorbid conditions had lower baseline physical health-related quality of life (62.7 ± 22.6 vs 84.1 ± 19.7; p < 0.001) and psychosocial health-related quality of life (68.4 ± 14.1 vs 81.2 ± 15.3; p < 0.001) than reference norms, whereas children without such conditions had baseline scores similar to reference norms. Children with complex chronic comorbid conditions recovered to their baseline health-related quality of life, whereas children without such conditions did not (physical health-related quality of life 75.3 ± 23.7 vs 83.2 ± 20.1; p = 0.008 and psychosocial health-related quality of life 74.5 ± 18.7 vs 80.5 ± 17.9; p = 0.006). Age less than 2 years was independently associated with higher month 12 physical health-related quality of life, and abnormal neurologic examination and neurologic injury suspected by a healthcare provider during the PICU course were independently associated with lower month 12 physical health-related quality of life. Treatment of increased intracranial pressure and medical device use at month 1 were independently associated with lower month 12 psychosocial health-related quality of life.

Conclusions: Physical and psychosocial health-related quality of life were reduced among children during the first year following community-acquired septic shock compared with reference norms, although many recovered to baseline. Risk factors for poor health-related quality of life included neurologic complications during the hospitalization and dependence on a medical device 1 month postadmission.
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http://dx.doi.org/10.1097/PCC.0000000000002374DOI Listing
October 2020

Design and Rationale for Common Data Elements for Clinical Research in Pediatric Critical Care Medicine.

Pediatr Crit Care Med 2020 11;21(11):e1038-e1041

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

Objectives: Common data elements are a combination of a precisely defined question paired with a specified set of responses. Common data elements contribute to the National Institutes of Health-supported principle of Findable, Accessible, Interoperable, and Reusableness of research data. Routine use of Common data elements and standardized definitions within pediatric critical care research are likely to promote collaboration, improve quality, and consistency of data collection, improve overall efficiency of study or trial setup, and facilitate cross-study comparisons, meta-analysis, and merging of study cohorts. The purpose of this Pediatric Critical Care Medicine Perspective is to establish a road map for the development of multinational, multidisciplinary consensus-based common data elements that could be adapted for use within any pediatric critical care subject area.

Methods: We describe a multistep process for the creation of "core domains" of research (e.g. patient outcomes, health-related conditions, or aspects of health) and the development of common data elements within each core domain. We define a tiered approach to data collection based on relevance of each common data element to future studies and clinical practice within the field of interest. Additionally, we describe the use of the Delphi methods to achieve consensus of these common data element documents using an international, multidisciplinary panel of experts.
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http://dx.doi.org/10.1097/PCC.0000000000002455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609513PMC
November 2020

Longitudinal Trajectories of Caregiver Distress and Family Functioning After Community-Acquired Pediatric Septic Shock.

Pediatr Crit Care Med 2020 09;21(9):787-796

Department of Pediatrics, Seattle Children's Hospital, Seattle Research Institute, University of Washington School of Medicine, Seattle, WA.

Objectives: To identify trajectories and correlates of caregiver distress and family functioning in families of children who survived community-acquired septic shock. We hypothesized that: 1) a substantial subset of families would demonstrate trajectories of persistent elevated caregiver distress and impaired family functioning 12 months after hospitalization and 2) sociodemographic and clinical risk factors would be associated with trajectories of persistent distress and family dysfunction.

Design: Prospective cohort.

Setting: Fourteen PICUs in the United States.

Patients: Caregivers of 260 children who survived community-acquired septic shock.

Interventions: None.

Measurements And Main Results: Caregivers completed ratings of distress on the Brief Symptom Inventory and of family functioning on the Family Assessment Device at baseline, 1, 3, 6, and 12 months after hospitalization. Results from group-based trajectory modeling indicated that 67% of the current sample was characterized by persistent low caregiver distress, 26% by persistent moderate to high distress that remained stable across 12 months (high-risk caregiver distress group), and 8% by initial high distress followed by gradual recovery. Forty percent of the sample was characterized by stable high family functioning, 15% by persistent high dysfunction across 12 months (high-risk family functioning group), 12% by gradually improving functioning, and 32% by deteriorating function over time. Independently of age, child race was associated with membership in the high-risk caregiver distress group (non-white/Hispanic; effect size, -0.12; p = 0.010). There were no significant sociodemographic or clinical correlates of the high-risk family functioning group in multivariable analyses.

Conclusions: Although the majority of families whose children survived community-acquired septic shock were characterized by resilience, a subgroup demonstrated trajectories of persistently elevated distress and family dysfunction during the 12 months after hospitalization. Results suggest a need for family-based psychosocial screening after pediatric septic shock to identify and support at-risk families.
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http://dx.doi.org/10.1097/PCC.0000000000002404DOI Listing
September 2020

Impact of Bilateral Infiltrates on Inflammatory Biomarker Levels and Clinical Outcomes of Children With Oxygenation Defect.

Crit Care Med 2020 Jun;48(6):e498-e504

Division of Critical Care Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI.

Objectives: The 2015 definition for pediatric acute respiratory distress syndrome did not require the presence of bilateral infiltrates. We tested the hypothesis that pediatric patients meeting oxygenation criteria for pediatric acute respiratory distress syndrome but without bilateral infiltrates would have different inflammatory biomarker levels and clinical outcomes than those with bilateral infiltrates.

Design: Secondary analysis of a prospective cohort study.

Setting: Twenty-two PICUs.

Patients: Four-hundred forty-six patients age 2 weeks to 17 years intubated for respiratory failure with oxygenation index greater than or equal to 4 or oxygenation saturation index greater than or equal to 5 on the day of intubation or the day after.

Interventions: None.

Measurements And Main Results: Patients with bilateral infiltrates, either on the day of intubation or within the following 2 days, were compared with children who never developed bilateral infiltrates. Two analyses were performed to test 1) whether bilateral infiltrates are associated with elevated interleukin-1 receptor antagonist or interleukin-8 and 2) whether bilateral infiltrates are associated with worse clinical outcomes. Patients with bilateral infiltrates more often had a primary diagnosis of pneumonia (41% vs 28%; p = 0.02) and less often asthma (8% vs 23%; p < 0.01). After controlling for age, gender, and primary diagnosis, interleukin-1 receptor antagonist was higher on study days 1 and 2 in patients with bilateral infiltrates. There was no difference in interleukin-8 levels. After adjusting for age, gender, Pediatric Risk of Mortality score, and severity of oxygenation defect, presence of bilateral infiltrates was associated with longer duration of mechanical ventilation in survivors (hazard ratio, 0.64; 95% CI, 0.49-0.82; p < 0.01); this association was independent of primary diagnosis. Overall mortality was 9%; mortality was higher in those without bilateral infiltrates (14% vs 8%; p = 0.04).

Conclusions: Children meeting pediatric acute respiratory distress syndrome oxygenation criteria with bilateral infiltrates on chest radiograph experience a more intense early inflammatory response. Bilateral infiltrates are associated with longer time on the ventilator independent of oxygenation defect severity.
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http://dx.doi.org/10.1097/CCM.0000000000004316DOI Listing
June 2020

Surfactant Protein D Is Associated With Severe Pediatric ARDS, Prolonged Ventilation, and Death in Children With Acute Respiratory Failure.

Chest 2020 Sep 8;158(3):1027-1035. Epub 2020 Apr 8.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI. Electronic address:

Background: Elevated surfactant protein D (SP-D) is a relatively specific indicator of lung injury and is associated with both acute and chronic lung disease in adults and respiratory distress syndrome in premature infants. The relationship between plasma SP-D and lung injury in children with acute respiratory failure is unclear.

Research Question: Is plasma SP-D associated with lung injury or outcome in children with acute respiratory failure?

Study Design And Methods: This was a prospective cohort study in children 2 weeks to 17 years of age with acute respiratory failure who participated in the BALI multi-center study. Analyses were done using SP-D levels in plasma from the first sample taken on either the day of intubation or one of the following 2 days. SP-D level was measured by enzyme-linked immunosorbent assay.

Results: Plasma samples from 350 patients were used in the analysis; 233 had pediatric ARDS (PARDS). SP-D levels varied across primary diagnoses (P < .001). Elevated SP-D levels were associated with severe PARDS after adjusting for age, pediatric risk of mortality III (PRISM-III), and primary diagnosis (OR = 1.02; CI = 1.01-1.04; P = .011). Multivariable analyses also indicated that elevated SP-D levels were associated with death (OR = 1.02; CI = 1.01-1.04; P = .004), duration of mechanical ventilation (P = .012), PICU length of stay (P = .019), and highest oxygenation index (P = .040). SP-D levels also correlated with age (r = 0.16, P = .002).

Interpretation: Elevated plasma SP-D levels are associated with severe PARDS and poor outcomes in children with acute respiratory failure. Future studies will determine whether SP-D can be used to predict the degree of lung injury or response to treatment and whether SP-D is useful in identifying PARDS endotypes.
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http://dx.doi.org/10.1016/j.chest.2020.03.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478231PMC
September 2020

Predicting Mortality in Children With Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

Crit Care Med 2020 06;48(6):e514-e522

Department of Pediatrics and Public Health Science, Division of Pediatric Critical Care Medicine, Penn State Hershey Children's Hospital, Hershey, PA.

Objectives: Pediatric acute respiratory distress syndrome is heterogeneous, with a paucity of risk stratification tools to assist with trial design. We aimed to develop and validate mortality prediction models for patients with pediatric acute respiratory distress syndrome.

Design: Leveraging additional data collection from a preplanned ancillary study (Version 1) of the multinational Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology study, we identified predictors of mortality. Separate models were built for the entire Version 1 cohort, for the cohort excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths. Models were externally validated in a cohort of intubated pediatric acute respiratory distress syndrome patients from the Children's Hospital of Philadelphia.

Setting: The derivation cohort represented 100 centers worldwide; the validation cohort was from Children's Hospital of Philadelphia.

Patients: There were 624 and 640 subjects in the derivation and validation cohorts, respectively.

Interventions: None.

Measurements And Main Results: The model for the full cohort included immunocompromised status, Pediatric Logistic Organ Dysfunction 2 score, day 0 vasopressor-inotrope score and fluid balance, and PaO2/FIO2 6 hours after pediatric acute respiratory distress syndrome onset. This model had good discrimination (area under the receiver operating characteristic curve 0.82), calibration, and internal validation. Models excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths also demonstrated good discrimination (all area under the receiver operating characteristic curve ≥ 0.84) and calibration. In the validation cohort, models for intubated pediatric acute respiratory distress syndrome (including and excluding neurologic deaths) had excellent discrimination (both area under the receiver operating characteristic curve ≥ 0.85), but poor calibration. After revision, the model for all intubated subjects remained miscalibrated, whereas the model excluding neurologic deaths showed perfect calibration. Mortality models also stratified ventilator-free days at 28 days in both derivation and validation cohorts.

Conclusions: We describe predictive models for mortality in pediatric acute respiratory distress syndrome using readily available variables from day 0 of pediatric acute respiratory distress syndrome which outperform severity of illness scores and which demonstrate utility for composite outcomes such as ventilator-free days. Models can assist with risk stratification for clinical trials.
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http://dx.doi.org/10.1097/CCM.0000000000004345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237024PMC
June 2020

Inhaled Nitric Oxide Use in Pediatric Hypoxemic Respiratory Failure.

Pediatr Crit Care Med 2020 08;21(8):708-719

Division of Pediatric Critical Care Medicine, Department of Pediatrics, Children's National Health System, Washington, DC.

Objectives: To characterize contemporary use of inhaled nitric oxide in pediatric acute respiratory failure and to assess relationships between clinical variables and outcomes. We sought to study the relationship of inhaled nitric oxide response to patient characteristics including right ventricular dysfunction and clinician responsiveness to improved oxygenation. We hypothesize that prompt clinician responsiveness to minimize hyperoxia would be associated with improved outcomes.

Design: An observational cohort study.

Setting: Eight sites of the Collaborative Pediatric Critical Care Research Network.

Patients: One hundred fifty-one patients who received inhaled nitric oxide for a primary respiratory indication.

Measurements And Main Results: Clinical data were abstracted from the medical record beginning at inhaled nitric oxide initiation and continuing until the earliest of 28 days, ICU discharge, or death. Ventilator-free days, oxygenation index, and Functional Status Scale were calculated. Echocardiographic reports were abstracted assessing for pulmonary hypertension, right ventricular dysfunction, and other cardiovascular parameters. Clinician responsiveness to improved oxygenation was determined. One hundred thirty patients (86%) who received inhaled nitric oxide had improved oxygenation by 24 hours. PICU mortality was 29.8%, while a new morbidity was identified in 19.8% of survivors. Among patients who had echocardiograms, 27.9% had evidence of pulmonary hypertension, 23.1% had right ventricular systolic dysfunction, and 22.1% had an atrial communication. Moderate or severe right ventricular dysfunction was associated with higher mortality. Clinicians responded to an improvement in oxygenation by decreasing FIO2 to less than 0.6 within 24 hours in 71% of patients. Timely clinician responsiveness to improved oxygenation with inhaled nitric oxide was associated with more ventilator-free days but not less cardiac arrests, mortality, or additional morbidity.

Conclusions: Clinician responsiveness to improved oxygenation was associated with less ventilator days. Algorithms to standardize ventilator management may improve signal to noise ratios in future trials enabling better assessment of the effect of inhaled nitric oxide on patient outcomes. Additionally, confining studies to more selective patient populations such as those with right ventricular dysfunction may be required.
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http://dx.doi.org/10.1097/PCC.0000000000002310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416469PMC
August 2020

Development of a core outcome set for pediatric critical care outcomes research.

Contemp Clin Trials 2020 04 5;91:105968. Epub 2020 Mar 5.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington School of Medicine and Center for Child Health, Behavior, and Development, Seattle Children's Research Institute, 4800 Sand Point Way NE, Seattle, WA 98105, United States of America. Electronic address:

Background: Pediatric Intensive Care Unit (PICU) teams provide care for critically ill children with diverse and often complex medical and surgical conditions. Researchers often lack guidance on an approach to select the best outcomes when evaluating this critically ill population. Studies would be enhanced by incorporating multi-stakeholder preferences to better evaluate clinical care. This manuscript outlines the methodology currently being used to develop a PICU Core Outcome Set (COS). This PICU COS utilizes mixed methods, an inclusive stakeholder approach, and a modified Delphi consensus process that will serve as a resource for PICU research programs.

Methods: A Scoping Review of the PICU literature evaluating outcomes after pediatric critical illness, a qualitative study interviewing PICU survivors and their parents, and other relevant literature will serve to inform a modified, international Delphi consensus process. The Delphi process will derive a set of minimum domains for evaluation of outcomes of critically ill children and their families. Delphi respondents include researchers, multidisciplinary clinicians, families and former patients, research funding agencies, payors, and advocates. Consensus meetings will refine and finalize the domains of the COS, outline a battery instruments for use in future studies, and prepare for extensive dissemination for broad implementation.

Discussion: The PICU COS will be a guideline resource for investigators to assure that outcomes most important to all stakeholders are considered in PICU clinical research in addition to those deemed most important to individual scientists.

Trial Registration: COMET database (http://www.comet-initiative.org/, Record ID 1131, 01/01/18).
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http://dx.doi.org/10.1016/j.cct.2020.105968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313715PMC
April 2020

Variability in chest compression rate calculations during pediatric cardiopulmonary resuscitation.

Resuscitation 2020 04 20;149:127-133. Epub 2020 Feb 20.

Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States.

Aim: The mathematical method used to calculate chest compression (CC) rate during cardiopulmonary resuscitation varies in the literature and across device manufacturers. The objective of this study was to determine the variability in calculated CC rates by applying four published methods to the same dataset.

Methods: This study was a secondary investigation of the first 200 pediatric cardiac arrest events with invasive arterial line waveform data in the ICU-RESUScitation Project (NCT02837497). Instantaneous CC rates were calculated during periods of uninterrupted CCs. The defined minimum interruption length affects rate calculation (e.g., if an interruption is defined as a break in CCs ≥ 2 s, the lowest possible calculated rate is 30 CCs/min). Average rates were calculated by four methods: 1) rate with an interruption defined as ≥ 1 s; 2) interruption ≥ 2 s; 3) interruption ≥ 3 s; 4) method #3 excluding top and bottom quartiles of calculated rates. American Heart Association Guideline-compliant rate was defined as 100-120 CCs/min. A clinically important change was defined as ±5 CCs/min. The percentage of events and epochs (30 s periods) that changed Guideline-compliant status was calculated.

Results: Across calculation methods, mean CC rates (118.7-119.5/min) were similar. Comparing all methods, 14 events (7%) and 114 epochs (6%) changed Guideline-compliant status.

Conclusion: Using four published methods for calculating CC rate, average rates were similar, but 7% of events changed Guideline-compliant status. These data suggest that a uniform calculation method (interruption ≥ 1 s) should be adopted to decrease variability in resuscitation science.
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http://dx.doi.org/10.1016/j.resuscitation.2020.01.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296394PMC
April 2020

Trajectory of Mortality and Health-Related Quality of Life Morbidity Following Community-Acquired Pediatric Septic Shock.

Crit Care Med 2020 03;48(3):329-337

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Utah, Salt Lake City, UT.

Objectives: In-hospital pediatric sepsis mortality has decreased substantially, but long-term mortality and morbidity among children initially surviving sepsis, is unknown. Accordingly, the Life After Pediatric Sepsis Evaluation investigation was conducted to describe the trajectory of mortality and health-related quality of life morbidity for children encountering community-acquired septic shock.

Design: Prospective, cohort-outcome study, conducted 2013-2017.

Setting: Twelve academic PICUs in the United States.

Patients: Critically ill children, 1 month to 18 years, with community-acquired septic shock requiring vasoactive-inotropic support.

Interventions: Demographic, infection, illness severity, organ dysfunction, and resource utilization data were collected daily during PICU admission. Serial parent proxy-report health-related quality of life assessments were obtained at baseline, 7 days, and 1, 3, 6, and 12 months following PICU admission utilizing the Pediatric Quality of Life Inventory or Stein-Jessop Functional Status Scale.

Measurements And Main Results: Among 389 children enrolled, mean age was 7.4 ± 5.8 years; 46% were female; 18% were immunocompromised; and 51% demonstrated chronic comorbidities. Baseline Pediatric Overall Performance Category was normal in 38%. Median (Q1-Q3) Pediatric Risk of Mortality and Pediatric Logistic Organ Dysfunction scores at PICU admission were 11.0 (6.0-17.0) and 9.0 (6.0-11.0); durations of vasoactive-inotropic and mechanical ventilation support were 3.0 days (2.0-6.0 d) and 8.0 days (5.0-14.0 d); and durations of PICU and hospital stay were 9.4 days (5.6-15.4 d) and 15.7 days (9.2-26.0 d). At 1, 3, 6, and 12 months following PICU admission for the septic shock event, 8%, 11%, 12%, and 13% of patients had died, while 50%, 37%, 30%, and 35% of surviving patients had not regained their baseline health-related quality of life.

Conclusions: This investigation provides the first longitudinal description of long-term mortality and clinically relevant, health-related quality of life morbidity among children encountering community-acquired septic shock. Although in-hospital mortality was 9%, 35% of survivors demonstrated significant, health-related quality of life deterioration from baseline that persisted at least 1 year following hospitalization for septic shock.
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http://dx.doi.org/10.1097/CCM.0000000000004123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164680PMC
March 2020

Critical Illness Factors Associated With Long-Term Mortality and Health-Related Quality of Life Morbidity Following Community-Acquired Pediatric Septic Shock.

Crit Care Med 2020 03;48(3):319-328

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Utah, Salt Lake City, UT.

Objectives: A companion article reports the trajectory of long-term mortality and significant health-related quality of life disability among children encountering septic shock. In this article, the investigators examine critical illness factors associated with these adverse outcomes.

Design: Prospective, cohort-outcome study, conducted 2013-2017.

Setting: Twelve United States academic PICUs.

Patients: Critically ill children, 1 month to 18 years, with community-acquired septic shock requiring vasoactive-inotropic support.

Interventions: Illness severity, organ dysfunction, and resource utilization data were collected during PICU admission. Change from baseline health-related quality of life at the month 3 follow-up was assessed by parent proxy-report employing the Pediatric Quality of Life Inventory or the Stein-Jessop Functional Status Scale.

Measurements And Main Results: In univariable modeling, critical illness variables associated with death and/or persistent, serious health-related quality of life deterioration were candidates for multivariable modeling using Bayesian information criterion. The most clinically relevant multivariable models were selected among models with near-optimal statistical fit. Three months following septic shock, 346 of 389 subjects (88.9%) were alive and 43 of 389 had died (11.1%); 203 of 389 (52.2%) had completed paired health-related quality of life surveys. Pediatric Risk of Mortality, cumulative Pediatric Logistic Organ Dysfunction scores, PICU and hospital durations of stay, maximum and cumulative vasoactive-inotropic scores, duration of mechanical ventilation, need for renal replacement therapy, extracorporeal life support or cardiopulmonary resuscitation, and appearance of pathologic neurologic signs were associated with adverse outcomes in univariable models. In multivariable regression analysis (odds ratio [95% CI]), summation of daily Pediatric Logistic Organ Dysfunction scores, 1.01/per point (1.01-1.02), p < 0.001; highest vasoactive-inotropic score, 1.02/per point (1.00-1.04), p = 0.003; and any acute pathologic neurologic sign/event, 5.04 (2.15-12.01), p < 0.001 were independently associated with death or persistent, serious deterioration of health-related quality of life at month 3.

Conclusions And Relevance: Biologically plausible factors related to sepsis-associated critical illness organ dysfunction and its treatment were associated with poor outcomes at month 3 follow-up among children encountering septic shock.
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http://dx.doi.org/10.1097/CCM.0000000000004122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089387PMC
March 2020

Structured Chart Review: Assessment of a Structured Chart Review Methodology.

Hosp Pediatr 2020 01;10(1):61-69

School of Medicine and Health Sciences, The George Washington University and Children's National Health System, Washington, District of Columbia;

Background And Objectives: Chart reviews are frequently used for research, care assessments, and quality improvement activities despite an absence of data on reliability and validity. We aim to describe a structured chart review methodology and to establish its validity and reliability.

Methods: A generalizable structured chart review methodology was designed to evaluate causes of morbidity or mortality and to identify potential therapeutic advances. The review process consisted of a 2-tiered approach with a primary review completed by a site physician and a short secondary review completed by a central physician. A total of 327 randomly selected cases of known mortality or new morbidities were reviewed. Validity was assessed by using postreview surveys with a Likert scale. Reliability was assessed by percent agreement and interrater reliability.

Results: The primary reviewers agreed or strongly agreed in 94.9% of reviews that the information to form a conclusion about pathophysiological processes and therapeutic advances could be adequately found. They agreed or strongly agreed in 93.2% of the reviews that conclusions were easy to make, and confidence in the process was 94.2%. Secondary reviewers made modifications to 36.6% of cases. Duplicate reviews ( = 41) revealed excellent percent agreement for the causes (80.5%-100%) and therapeutic advances (68.3%-100%). κ statistics were strong for the pathophysiological categories but weaker for the therapeutic categories.

Conclusions: A structured chart review by knowledgeable primary reviewers, followed by a brief secondary review, can be valid and reliable.
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http://dx.doi.org/10.1542/hpeds.2019-0225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931034PMC
January 2020

Comprehensive Prognostication in Critically Ill Pediatric Hematopoietic Cell Transplant Patients: Results from Merging the Center for International Blood and Marrow Transplant Research (CIBMTR) and Virtual Pediatric Systems (VPS) Registries.

Biol Blood Marrow Transplant 2020 02 26;26(2):333-342. Epub 2019 Sep 26.

Department of Pediatrics, Division of Allergy, Immunology, and Blood and Marrow Transplantation, University of California, San Francisco, San Francisco, California.

Critically ill pediatric allogeneic hematopoietic cell transplant (HCT) patients may benefit from early and aggressive interventions aimed at reversing the progression of multiorgan dysfunction. Therefore, we evaluated 25 early risk factors for pediatric intensive care unit (PICU) mortality to improve mortality prognostication. We merged the Virtual Pediatric Systems and Center for International Blood and Marrow Transplant Research databases and analyzed 936 critically ill patients ≤21 years of age who had undergone allogeneic HCT and subsequently required PICU admission between January 1, 2009, and December 31, 2014. Of 1532 PICU admissions, the overall PICU mortality rate was 17.4% (95% confidence interval [CI], 15.6% to 19.4%) but was significantly higher for patients requiring mechanical ventilation (44.0%), renal replacement therapy (56.1%), or extracorporeal life support (77.8%). Mortality estimates increased significantly the longer that patients remained in the PICU. Of 25 HCT- and PICU-specific characteristics available at or near the time of PICU admission, moderate/severe pre-HCT renal injury, pre-HCT recipient cytomegalovirus seropositivity, <100-day interval between HCT and PICU admission, HCT for underlying acute myeloid leukemia, and greater admission organ dysfunction as approximated by the Pediatric Risk of Mortality 3 score were each independently associated with PICU mortality. A multivariable model using these components identified that patients in the top quartile of risk had 3 times greater mortality than other patients (35.1% versus 11.5%, P < .001, classification accuracy 75.2%; 95% CI, 73.0% to 77.4%). These data improve our working knowledge of the factors influencing the progression of critical illness in pediatric allogeneic HCT patients. Future investigation aimed at mitigating the effect of these risk factors is warranted.
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http://dx.doi.org/10.1016/j.bbmt.2019.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943183PMC
February 2020

Plasma total fibroblast growth factor 23 levels are associated with acute kidney injury and mortality in children with acute respiratory distress syndrome.

PLoS One 2019 5;14(9):e0222065. Epub 2019 Sep 5.

Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America.

Acute respiratory distress syndrome (ARDS) has high rates of mortality and multisystem morbidity. Pre-clinical data suggest that fibroblast growth factor 23 (FGF23) may contribute to pulmonary pathology, and FGF23 is associated with mortality and morbidity, including acute kidney injury (AKI), in non-ARDS cohorts. Here, we assess whether FGF23 is associated with AKI and/or mortality in a cohort of 161 pediatric ARDS patients. Plasma total (intact + C-terminal) FGF23 and intact FGF23 concentrations were measured within 24 hours of ARDS diagnosis (Day 1), and associations with Day 3 AKI and 60-day mortality were evaluated. 35 patients (22%) developed AKI by 3 days post-ARDS diagnosis, and 25 (16%) died by 60 days post-ARDS diagnosis. In unadjusted models, higher Day 1 total FGF23 was associated with Day 3 AKI (odds ratio (OR) 2.22 [95% confidence interval (CI) 1.62, 3.03], p<0.001), but Day 1 intact FGF23 was not. In a model adjusted for demographics and disease severity, total FGF23 remained associated with AKI (OR 1.52 [95% CI 1.02, 2.26], p = 0.039). In unadjusted models, both higher Day 1 total and intact FGF23 were associated with 60-day mortality (OR 1.43 [95% CI 1.07, 1.91], p = 0.014; and OR 1.44 [95% CI 1.02, 2.05], p = 0.039, respectively). In the adjusted model, only total FGF23 remained associated with 60-day mortality (OR 1.62 [95% CI 1.07, 2.45], p = 0.023). In a subgroup analysis of patients with Day 1 plasma IL-6 concentrations available, inflammation partially mediated the association between total FGF23 and AKI. Our data suggest both inflammation-dependent and inflammation-independent associations between total FGF23 and clinical outcomes in pediatric ARDS patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222065PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728039PMC
March 2020

The association of immediate post cardiac arrest diastolic hypertension and survival following pediatric cardiac arrest.

Resuscitation 2019 08 6;141:88-95. Epub 2019 Jun 6.

Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States.

Aim: In-hospital cardiac arrest occurs in >5000 children each year in the US and almost half will not survive to discharge. Animal data demonstrate that an immediate post-resuscitation burst of hypertension is associated with improved survival. We aimed to determine if systolic and diastolic invasive arterial blood pressures immediately (0-20 min) after return of spontaneous circulation (ROSC) are associated with survival and neurologic outcomes at hospital discharge.

Methods: This is a secondary analysis of the Pediatric Intensive Care Quality of CPR (PICqCPR) study of invasively measured blood pressures during intensive care unit CPR. Patients were eligible if they achieved ROSC and had at least one invasively measured blood pressure within the first 20 min following ROSC. Post-ROSC blood pressures were normalized for age, sex and height. "Immediate hypertension" was defined as at least one systolic or diastolic blood pressure >90th percentile. The primary outcome was survival to hospital discharge.

Results: Of 102 children, 70 (68.6%) had at least one episode of immediate post-CPR diastolic hypertension. After controlling for pre-existing hypotension, duration of CPR, calcium administration, and first documented rhythm, patients with immediate post-CPR diastolic hypertension were more likely to survive to hospital discharge (79.3% vs. 54.5%; adjusted OR = 2.93; 95%CI, 1.16-7.69).

Conclusions: In this post hoc secondary analysis of the PICqCPR study, 68.6% of subjects had diastolic hypertension within 20 min of ROSC. Immediate post-ROSC hypertension was associated with increased odds of survival to discharge, even after adjusting for covariates of interest.
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http://dx.doi.org/10.1016/j.resuscitation.2019.05.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709525PMC
August 2019

Evaluation of Mannose Binding Lectin Gene Variants in Pediatric Influenza Virus-Related Critical Illness.

Front Immunol 2019 8;10:1005. Epub 2019 May 8.

Division of Critical Care Medicine, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital and Department of Anaesthesia, Harvard Medical School, Boston, MA, United States.

Mannose-binding lectin (MBL) is an innate immune protein with strong biologic plausibility for protecting against influenza virus-related sepsis and bacterial co-infection. In an autopsy cohort of 105 influenza-infected young people, carriage of the deleterious MBL gene _Gly54Asp("B") mutation was identified in 5 of 8 individuals that died from influenza-methicillin-resistant (MRSA) co-infection. We evaluated variants known to influence MBL levels with pediatric influenza-related critical illness susceptibility and/or severity including with bacterial co-infections. We enrolled children and adolescents with laboratory-confirmed influenza infection across 38 pediatric intensive care units from November 2008 to June 2016. We sequenced "low-producer" variants rs11003125("H/L"), rs7096206("Y/X"), rs1800450("B"), rs1800451("C"), rs5030737("D") in patients and biologic parents. We measured serum levels and compared complement activity in low-producing homozygotes ("B/B," "C/C") to HYA/HYA controls. We used a population control of 1,142 healthy children and also analyzed family trios (PBAT/HBAT) to evaluate disease susceptibility, and nested case-control analyses to evaluate severity. We genotyped 420 patients with confirmed influenza-related sepsis: 159 (38%) had acute lung injury (ALI), 165 (39%) septic shock, and 30 (7%) died. Although bacterial co-infection was diagnosed in 133 patients (32%), only MRSA co-infection ( = 33, 8% overall) was associated with death ( < 0.0001), present in 11 of 30 children that died (37%). variants predicted serum levels and complement activation as expected. We found no association between influenza-related critical illness susceptibility and variants using family trios (633 biologic parents) or compared to population controls. variants were not associated with admission illness severity, septic shock, ALI, or bacterial co-infection diagnosis. Carriage of low-MBL producing variants was not a risk factor for mortality, but children that died did have higher carriage of one or more B alleles (OR 2.3; = 0.007), including 7 of 11 with influenza MRSA-related death (vs. 2 of 22 survivors: OR 14.5, = 0.0002). variants that decrease MBL levels were not associated with susceptibility to pediatric influenza-related critical illness or with multiple measures of critical illness severity. We confirmed a prior report of higher B allele carriage in a relatively small number of young individuals with influenza-MRSA associated death.
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http://dx.doi.org/10.3389/fimmu.2019.01005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518443PMC
September 2020

A prospective investigation of interleukin-8 levels in pediatric acute respiratory failure and acute respiratory distress syndrome.

Crit Care 2019 04 17;23(1):128. Epub 2019 Apr 17.

Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, 1500 East Medical Center Dr, F6790/5243, Ann Arbor, MI, 48109, USA.

Background: The association of plasma interleukin-8 (IL-8), or IL-8 genetic variants, with pediatric acute respiratory distress syndrome (PARDS) in children with acute respiratory failure at risk for PARDS has not been examined. The purpose of this study was to examine the association of early and sequential measurement of plasma IL-8 and/or its genetic variants with development of PARDS and other clinical outcomes in mechanically ventilated children with acute respiratory failure.

Methods: This was a prospective cohort study of children 2 weeks to 17 years of age with acute airways and/or parenchymal lung disease done in 22 pediatric intensive care units participating in the multi-center clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). Plasma IL-8 levels were measured within 24 h of consent and 24 and 48 h later. DNA was purified from whole blood, and IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, were genotyped.

Results: Five hundred forty-nine patients were enrolled; 480 had blood sampling. Plasma IL-8 levels ranged widely from 4 to 7373 pg/mL. Highest IL-8 levels were observed on the day of intubation with subsequent tapering. Levels of IL-8 varied significantly across primary diagnoses with the highest levels occurring in patients with sepsis and the lowest levels in those with asthma. Plasma IL-8 was strongly correlated with oxygenation defect and severity of illness. IL-8 was consistently higher in PARDS patients compared to those without PARDS; levels were 4-12 fold higher in non-survivors compared to survivors. On multivariable analysis, IL-8 was independently associated with death, duration of mechanical ventilation, and PICU length of stay on all days measured, but was not associated with PARDS development. There was no association between the IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, and PARDS development or plasma IL-8 level.

Conclusions: When measured sequentially, plasma IL-8 was robustly associated with multiple, relevant clinical outcomes including mortality, but was not associated with PARDS development. The wide range of plasma IL-8 levels exhibited in this cohort suggests that further study into the heterogeneity of this patient population and its impact on individual responses to PARDS treatment is warranted.
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http://dx.doi.org/10.1186/s13054-019-2342-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471952PMC
April 2019

Short-Term Adverse Outcomes Associated With Hypoglycemia in Critically Ill Children.

Crit Care Med 2019 05;47(5):706-714

Division of Medical Critical Care, Department of Pediatrics, Boston Children's Hospital, Boston, MA.

Objectives: Previous studies report worse short-term outcomes with hypoglycemia in critically ill children. These studies relied on intermittent blood glucose measurements, which may have introduced detection bias. We analyzed data from the Heart And Lung Failure-Pediatric INsulin Titration trial to determine the association of hypoglycemia with adverse short-term outcomes in critically ill children.

Design: Nested case-control study.

Setting: Thirty-five PICUs. A computerized algorithm that guided the timing of blood glucose measurements and titration of insulin infusion, continuous glucose monitors, and standardized glucose infusion rates were used to minimize hypoglycemia.

Patients: Nondiabetic children with cardiovascular and/or respiratory failure and hyperglycemia. Cases were children with any hypoglycemia (blood glucose < 60 mg/dL), whereas controls were children without hypoglycemia. Each case was matched with up to four unique controls according to age group, study day, and severity of illness.

Interventions: None.

Measurements And Main Results: A total of 112 (16.0%) of 698 children who received the Heart And Lung Failure-Pediatric INsulin Titration protocol developed hypoglycemia, including 25 (3.6%) who developed severe hypoglycemia (blood glucose < 40 mg/dL). Of these, 110 cases were matched to 427 controls. Hypoglycemia was associated with fewer ICU-free days (median, 15.3 vs 20.2 d; p = 0.04) and fewer hospital-free days (0 vs 7 d; p = 0.01) through day 28. Ventilator-free days through day 28 and mortality at 28 and 90 days did not differ between groups. More children with insulin-induced versus noninsulin-induced hypoglycemia had zero ICU-free days (35.8% vs 20.9%; p = 0.008). Outcomes did not differ between children with severe versus nonsevere hypoglycemia or those with recurrent versus isolated hypoglycemia.

Conclusions: When a computerized algorithm, continuous glucose monitors and standardized glucose infusion rates were used to manage hyperglycemia in critically ill children with cardiovascular and/or respiratory failure, severe hypoglycemia (blood glucose < 40 mg/dL) was uncommon, but any hypoglycemia (blood glucose < 60 mg/dL) remained common and was associated with worse short-term outcomes.
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http://dx.doi.org/10.1097/CCM.0000000000003699DOI Listing
May 2019

Positive Cumulative Fluid Balance Is Associated With Mortality in Pediatric Acute Respiratory Distress Syndrome in the Setting of Acute Kidney Injury.

Pediatr Crit Care Med 2019 04;20(4):323-331

Division of Critical Care, Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA.

Objectives: As acute kidney injury and elevated cumulative fluid balance commonly co-occur in pediatric acute respiratory distress syndrome, we aimed to identify risk factors for their development and evaluate their independent relationships with mortality. We hypothesized that acute kidney injury and elevated cumulative fluid balance would be associated with markers of inflammation and that children with elevated cumulative fluid balance and concomitant acute kidney injury would have worse outcomes than other children.

Design: Prospective observational study using the pediatric Risk, Injury, Failure, Loss, End-Stage acute kidney injury classification.

Setting: Five academic PICUs.

Patients: Two-hundred sixty patients 1 month to 18 years old meeting the Berlin definition of acute respiratory distress syndrome between 2008 and 2014.

Interventions: None.

Measurements And Results: PICU mortality was 13% (34/260). Relative to survivors, nonsurvivors had greater cumulative fluid balance on day 3 of acute respiratory distress syndrome (+90.1 mL/kg; interquartile range 26.6-161.7 vs +44.9 mL/kg; interquartile range 10.0-111.3; p = 0.008) and also had higher prevalence of acute kidney injury on day 3 of acute respiratory distress syndrome (50% vs 23%; p = 0.001). On stratified analysis, greater cumulative fluid balance on day 3 of acute respiratory distress syndrome was associated with mortality among patients with concomitant acute kidney injury (+111.5 mL/kg for nonsurvivors; interquartile range 82.6-236.8 vs +58.5 mL/kg for survivors; interquartile range 0.9-176.2; p = 0.041) but not among patients without acute kidney injury (p = 0.308). The presence of acute kidney injury on acute respiratory distress syndrome day 3 was associated with mortality among patients with positive cumulative fluid balance (29.1% vs 10.4% mortality; p = 0.001) but not among patients with even or negative cumulative fluid balance (p = 0.430). Day 1 plasma interleukin-6 levels were associated with the development of day 3 positive cumulative fluid balance, day 3 acute kidney injury, and PICU mortality and the association between elevated day 1 interleukin-6 and PICU mortality was partially mediated by the interval development of day 3 positive cumulative fluid balance and day 3 acute kidney injury (p < 0.001).

Conclusions: In pediatric acute respiratory distress syndrome, elevated cumulative fluid balance on day 3 of acute respiratory distress syndrome is associated with mortality specifically in patients with concomitant acute kidney injury. Plasma interleukin-6 levels are associated with the development of positive cumulative fluid balance and acute kidney injury, suggesting a potential mechanism by which inflammation might predispose to mortality.
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http://dx.doi.org/10.1097/PCC.0000000000001845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454886PMC
April 2019

A Population Pharmacokinetic Analysis to Study the Effect of Extracorporeal Membrane Oxygenation on Cefepime Disposition in Children.

Pediatr Crit Care Med 2019 01;20(1):62-70

Metrum Research Group, Tariffville, CT.

Objectives: Limited data exist on the effects of extracorporeal membrane oxygenation on pharmacokinetics of cefepime in critically ill pediatric patients. The objective was to describe cefepime disposition in children treated with extracorporeal membrane oxygenation using population pharmacokinetic modeling.

Design: Multicenter, prospective observational study.

Setting: The pediatric and cardiac ICUs of six sites of the Collaborative Pediatric Critical Care Research Network.

Patients: Seventeen critically ill children (30 d to < 2 yr old) on extracorporeal membrane oxygenation who received cefepime as standard of care between January 4, 2014, and August 24, 2015, were enrolled.

Interventions: None.

Measurements And Main Results: A pharmacokinetic model was developed to evaluate cefepime disposition differences due to extracorporeal membrane oxygenation. A two-compartment model with linear elimination, weight effects on clearance, intercompartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (V2) adequately described the data. The typical value of clearance in this study was 7.1 mL/min (1.9 mL/min/kg) for a patient weighing 5.8 kg. This value decreased by approximately 40% with the addition of renal replacement therapy. The typical value for V1 was 1,170 mL. In the setting of blood transfusions, V1 increased by over two-fold but was reduced with increasing age of the extracorporeal membrane oxygenation circuit oxygenator.

Conclusions: Cefepime clearance was reduced in pediatric patients treated with extracorporeal membrane oxygenation compared with previously reported values in children not receiving extracorporeal membrane oxygenation. The model demonstrated that the age of the extracorporeal membrane oxygenation circuit oxygenator is inversely correlated to V1. For free cefepime, only 14 of the 19 doses (74%) demonstrated a fT_minimum inhibitory concentration of 16 mg/L, an appropriate target for the treatment of pseudomonal infections, for greater than 70% of the dosing interval. Pediatric patients on extracorporeal membrane oxygenation might benefit from the addition of therapeutic drug monitoring of cefepime to assure appropriate dosing.
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http://dx.doi.org/10.1097/PCC.0000000000001786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323642PMC
January 2019

Pulmonary Metagenomic Sequencing Suggests Missed Infections in Immunocompromised Children.

Clin Infect Dis 2019 05;68(11):1847-1855

Chan Zuckerberg Biohub, University of California-San Francisco School of Medicine.

Background: Despite improved diagnostics, pulmonary pathogens in immunocompromised children frequently evade detection, leading to significant mortality. Therefore, we aimed to develop a highly sensitive metagenomic next-generation sequencing (mNGS) assay capable of evaluating the pulmonary microbiome and identifying diverse pathogens in the lungs of immunocompromised children.

Methods: We collected 41 lower respiratory specimens from 34 immunocompromised children undergoing evaluation for pulmonary disease at 3 children's hospitals from 2014-2016. Samples underwent mechanical homogenization, parallel RNA/DNA extraction, and metagenomic sequencing. Sequencing reads were aligned to the National Center for Biotechnology Information nucleotide reference database to determine taxonomic identities. Statistical outliers were determined based on abundance within each sample and relative to other samples in the cohort.

Results: We identified a rich cross-domain pulmonary microbiome that contained bacteria, fungi, RNA viruses, and DNA viruses in each patient. Potentially pathogenic bacteria were ubiquitous among samples but could be distinguished as possible causes of disease by parsing for outlier organisms. Samples with bacterial outliers had significantly depressed alpha-diversity (median, 0.61; interquartile range [IQR], 0.33-0.72 vs median, 0.96; IQR, 0.94-0.96; P < .001). Potential pathogens were detected in half of samples previously negative by clinical diagnostics, demonstrating increased sensitivity for missed pulmonary pathogens (P < .001).

Conclusions: An optimized mNGS assay for pulmonary microbes demonstrates significant inoculation of the lower airways of immunocompromised children with diverse bacteria, fungi, and viruses. Potential pathogens can be identified based on absolute and relative abundance. Ongoing investigation is needed to determine the pathogenic significance of outlier microbes in the lungs of immunocompromised children with pulmonary disease.
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http://dx.doi.org/10.1093/cid/ciy802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784263PMC
May 2019