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OBJECTIVE: We previously demonstrated that dexamethasone treatment before cardiopulmonary bypass in children reduces the postoperative systemic inflammatory response. The purpose of this study was to test the hypothesis that dexamethasone administration before cardiopulmonary bypass in children correlates with a lesser degree of myocardial injury as measured by a decrease in cardiac troponin I release. DESIGN: A prospective, randomized, double-blind study. SETTING: The cardiac surgery operating room and intensive care unit of a pediatric referral hospital. SUBJECTS: Twenty-eight patients who underwent open-heart surgery for congenital heart defects. INTERVENTIONS: Patients received either placebo (group I, n = 13) or dexamethasone, 1 mg/kg iv (group II, n = 15), 1 hr before initiation of cardiopulmonary bypass. Plasma cardiac troponin I samples were obtained at three time points: immediately before study agent (sample 1), 10 mins after protamine sulfate administration after cardiopulmonary bypass (sample 2), and 24 hrs postoperatively (sample 3). MEASUREMENTS AND MAIN RESULTS: Mean cardiac troponin I levels (+/-sd) were significantly lower at sample time 3 in group II (dexamethasone; 33.4 +/- 20.0 ng/mL) vs. group I (control; 86.9 +/- 81.1) (p =.04). CONCLUSION: Dexamethasone administration before cardiopulmonary bypass in children resulted in a significant decrease in cardiac troponin I levels at 24 hrs postoperatively. We postulate that this may represent a decrease in myocardial injury, and, thus, a possible cardioprotective effect produced by dexamethasone. [ABSTRACT FROM AUTHOR]

Abstract: Open-heart surgery with cardiopulmonary bypass often leads to complications including pain, systemic inflammation, and organ damage. Traditionally managed with opioids, these pain relief methods bring potential long-term risks, prompting the exploration of alternative treatments. The legalization of cannabis in various regions has reignited interest in cannabinoids, such as cannabidiol, known for their anti-inflammatory, analgesic, and neuroprotective properties. Historical and ongoing research acknowledges the endocannabinoid system's crucial role in managing physiological processes, suggesting that cannabinoids could offer therapeutic benefits in postsurgical recovery. Specifically, cannabidiol has shown promise in managing pain, moderating immune responses, and mitigating ischemia/reperfusion injury, underscoring its potential in postoperative care. However, the translation of these findings into clinical practice faces challenges, highlighting the need for extensive research to establish effective, safe cannabinoid-based therapies for patients undergoing open-heart surgery. This narrative review advocates for a balanced approach, considering both the therapeutic potential of cannabinoids and the complexities of their integration into clinical settings., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The Society of Critical Care Medicine (SCCM) Reviewer Academy seeks to train and establish a community of trusted, reliable, and skilled peer reviewers with diverse backgrounds and interests to promote high-quality reviews for each of the SCCM journals. Goals of the Academy include building accessible resources to highlight qualities of excellent manuscript reviews; educating and mentoring a diverse group of healthcare professionals; and establishing and upholding standards for insightful and informative reviews. This manuscript will map the mission of the Reviewer Academy with a succinct summary of the importance of peer review, process of reviewing a manuscript, and the expected ethical standards of reviewers. We will equip readers to target concise, thoughtful feedback as peer reviewers, advance their understanding of the editorial process and inspire readers to integrate medical journalism into diverse professional careers., Competing Interests: Dr. Alexander has received funding from the National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (R13HD104432), Food and Drug Administration (FP01029501), US Department of Defense (W81XWH2210301), and unrestricted grants from the Extracorporeal Life Support Organization (ELSO). Her institution received funding from Novartis (end-point adjudication committee PANORAMA-HF) and she serves as the ELSO Treasurer of the Board of Directors. Dr. Barreto received funding from Wolters-Kluwer. Dr. Morrow’s institution received funding from the Society of Critical Care Medicine (SCCM) for her role as Senior Associate Editor for Pediatric Critical Care Medicine, the National Research Foundation of Southern Africa, and EuroQual; she received funding from the Brazilian Physiotherapy Association. Dr. Mayer’s institution received funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (no. K23-AR079583); he received support for article research from the NIH. Dr. Lane-Fall’s institution receives funding from NIH (R01HL153735, P30AG059302, UM1HL088957, U01OD033246, R01HD105446, R01HD109229), Agency for Healthcare Research and Quality (K12HS026372), Patient-Centered Outcomes Research Institute (21106), and the American Heart Association (962544). She serves as the Vice President of the Anesthesia Patient Safety Foundation and is on the Board of Directors of the Foundation for Anesthesia Education and Research. Dr. Kudchadkar has received funding from NIH/NICHD (R01HD103811) and NIH/NIDDK (R01DK132348). Dr. Rech has received research funding from Spero Pharmaceuticals. Ms. Napolitano receives funding from NIH (1R44HD105552, 1R21HD103927-01A1, 1R01HD106996) and FDA (5P50FD006427) and also has research/consulting relationships with Drager, Philips/Respironics, Timpel, Actuated Medical, and Vero-Biotech. Dr. Sorce disclosed that she is an SCCM Executive Board Member. Dr. Tasker is the Editor-in-Chief for Pediatric Critical Care Medicine. Dr. Buchman is Editor-in-Chief for Critical Care Medicine. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

Objectives: To compare the clinical, laboratory, and hemodynamic parameters during hospitalization for patients with multisystem inflammatory syndrome in children (MIS-C), across the Original/Alpha and the Delta variants of severe acute respiratory syndrome coronavirus 2 infection., Design: Retrospective cohort study., Setting: Single-center quaternary children's hospital., Patients: Children with MIS-C admitted from May 2020 to February 2021(Original and Alpha variant cohort) and August 2021 to November 2021 (Delta variant cohort)., Measurements and Main Results: Continuous vital sign measurements, laboratory results, medications data, and hospital outcomes from all subjects were evaluated. Of the 134 patients (102 with Original/Alpha and 32 with Delta), median age was 9 years, 75 (56%) were male, and 61 (46%) were Hispanics. The cohort with Original/Alpha variant had more males (61% vs 41%; p = 0.036) and more respiratory/musculoskeletal symptoms on presentation compared with the Delta variant ( p < 0.05). More patients in the Original/Alpha variant cohort received mechanical ventilation (16 vs 0; p = 0.009). Median hospital length of stay (LOS) was 7 days, and ICU LOS was 3 days for the entire cohort. ICU LOS was shorter in cohort with the Delta variant compared with the Original/Alpha variant (4 vs 2 d; p = 0.001). Only one patient had cardiac arrest, two needed extracorporeal membrane oxygenation, and two needed left ventricular assist device (Impella, Danvers, MA), all in the Original/Alpha variant cohort; no mortality occurred in the entire cohort. MIS-C cohort associated with the Delta variant had lower INR, prothrombin time, WBCs, sodium, phosphorus, and potassium median values ( p < 0.05) during hospitalization compared with the Original/Alpha variants. Hemodynamic assessment showed significant tachycardia in the Original/Alpha variants cohort compared with the Delta variant cohort ( p < 0.05)., Interventions: None., Conclusions: Patients with MIS-C associated with the Delta variants had lower severity during hospitalization compared with the Original/Alpha variant. Analysis of distinct trends in clinical and laboratory parameters with future variants of concerns will allow for potential modification of treatment protocol., Competing Interests: Dr. Jain’s institution received funding from the National Institute for Child Health and Human Development (1R61HD105593). Drs. Jain, Annapragada, Muscal, Vogel, and Rusin received support for article research from the National Institutes of Health (NIH). Dr. Annapragada’s institution received funding from the NIH (R61HD105593); he received funding from Alzeca and Sensulin; he disclosed that he is the inventor on numerous patents that are either licensed to or assigned to his employer, past employers, or other entities. Drs. Muscal and Vogel disclosed the off-label product use of Anakinra. Dr. Vogel’s institution received funding from the NIH; she disclosed the off-label product use of IV immunoglobulin for multisystem inflammatory syndrome in children. Dr. Rusin received funding from Medical Informatics Corp; he disclosed that he is the cofounder and Chief Technology Officer of Medical Informatics, and he disclosed that his wife is the cofounder and Chief Executive Officer of Medical Informatics. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: Opioids are used to manage pain, comfort, maintain devices, and decrease oxygen consumption around Norwood palliation (NP), but in high dose and prolonged exposure, they increase risk of tolerance and iatrogenic withdrawal syndrome (IAWS). Variability in practice for IAWS prevention potentially increases opioid dose and duration. We hypothesize that protocolized weaning with morphine (MOR) versus nonprotocolized methadone (MTD) is associated with reduction in opioid exposure., Design: A before-versus-after study of outcomes of patients weaned with protocolized MOR versus nonprotocolized MTD including subset analysis for those patients with complications postoperatively. Primary endpoints include daily, wean phase, and total morphine milligram equivalent (MMEq) dose, duration, and, secondarily, length of stay (LOS)., Setting: Quaternary-care pediatric cardiac ICU., Patients: Neonates undergoing single-ventricle palliation., Interventions: Introduction of IAWS prevention protocol., Measurements and Main Results: Analysis included 54 patients who underwent the NP in 2017-2018 including the subset analysis of 34 who had a complicated postoperative course. The total and wean phase opioid doses for the MTD group were significantly higher than that for the MOR group: 258 versus 22 and 115 versus 6 MMEq/kg; p < 0.001. Duration of opioid exposure was 63 days in the MTD group and 12 days in MOR group (p < 0.001). Subanalysis of the complicated subset also identifies higher total and wean dose for MTD group (293 vs 41 and 116 vs 7 MMEq/kg; p < 0.001) with a longer duration (65 vs 22 days; p = 0.001). Within the subset, LOS was 55% longer in the MTD group than that in the MOR group (150 vs 67 d; p = 0.01) and not different in the uncomplicated group., Conclusions: After complex NP, a protocolized opioid weaning using MOR versus MTD is associated with 65% shorter opioid duration, 10-fold decreased dose, and shortened LOS., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

Background: Acute decompensated heart failure (ADHF) is a highly morbid condition among adults. Little is known about outcomes in children with ADHF. We analyzed the Pediatric Cardiac Critical Care Consortium registry to determine the epidemiology, contemporary treatments, and predictors of mortality in critically ill children with ADHF., Methods: Cardiac intensive care unit (CICU) patients ≤18 years of age meeting Pediatric Cardiac Critical Care Consortium criteria for ADHF were included. ADHF was defined as systolic or diastolic dysfunction requiring continuous vasoactive or diuretic infusion, respiratory support, or mechanical circulatory support. Demographics, diagnosis, therapies, complications, and mortality are described for the cohort. Predictors of CICU mortality were identified using logistic regression., Results: Among 26 294 consecutive admissions (23 centers), 1494 (6%) met criteria for analysis. Median age was 0.93 years (interquartile range, 0.1-9.3 years). Patients with congenital heart disease (CHD) comprised 57% of the cohort. Common therapies included the following: vasoactive infusions (88%), central venous catheters (86%), mechanical ventilation (59%), and high flow nasal cannula (46%). Common complications were arrhythmias (19%), cardiac arrest (10%), sepsis (7%), and acute renal failure requiring dialysis (3%). Median length of CICU stay was 7.9 days (interquartile range, 3-18 days) and the CICU readmission rate was 22%. Overall, CICU mortality was 15% although higher for patients with CHD versus non-CHD (19% versus 11%; P <0.001). Independent risk factors associated with CICU mortality included age <30 days, CHD, vasoactive infusions, ventricular tachycardia, mechanical ventilation, sepsis, pulmonary hypertension, extracorporeal membrane oxygenation, and cardiac arrest., Conclusions: ADHF in children is characterized by comorbidities, high mortality rates, and frequent readmission, especially among patients with CHD. Opportunities exist to determine best practices around appropriate use of mechanical support, cardiac arrest prevention, and optimal heart transplantation candidacy to improve outcomes for these patients.

Objectives: Acetaminophen is ubiquitously used as antipyretic/analgesic administered IV to patients undergoing surgery and to critically ill patients when enteral routes are not possible. Widely believed to be safe and free of adverse side effects, concerns have developed in adult literature regarding the association of IV acetaminophen and transient hypotension. We hypothesize that there are hemodynamic effects after IV acetaminophen in the PICU and assess the prevalence of such in a large pediatric cardiovascular ICU population using high-fidelity data., Design: Observational study analyzing an enormous set of continuous physiologic data including millions of beat to beat blood pressures surrounding medication administration., Setting: Quaternary pediatric cardiovascular ICU between January 1, 2013, and November 13, 2017., Patients: All patients less than or equal to 18 years old who received IV acetaminophen. Mechanical support devices excluded., Interventions: None., Measurements and Main Results: Physiologic vital sign data were analyzed in 5-minute intervals starting 60 minutes before through 180 minutes after completion. Hypotension defined as mean arterial pressure -15% from baseline and relative hypotension defined -10%. Only doses where patients received no other medications, including vasopressors, within the previous hour were included. t test and a correlation matrix were used to eliminate correlated factors before a logistic regression analysis was performed. Six-hundred eight patients received 777 IV acetaminophen doses. Median age was 8.8 months (interquartile range, 2-62 mo) with a dose of 12.5 mg/kg (interquartile range, 10-15 mg/kg). Data were normalized for age and reference values. One in 20 doses (5%) were associated with hypotension, and one in five (20%) associated with relative hypotension. Univariate analysis revealed hypotension associated with age, baseline mean arterial pressure, and skin temperature (p = 0.05, 0.01, and 0.09). Logistic regression revealed mean arterial pressure (p = 0.01) and age (p = 0.05) remained predictive for hypotension., Conclusions: In isolation of other medication, a hemodynamic response to IV acetaminophen has a higher prevalence in critically ill children with cardiac disease than previously thought and justifies controlled studies in the perioperative and critical care setting. The added impact on individual patient hemodynamics and physiologic instability will require further study.

Objectives: Children with medical cardiac disease experience poorer survival to hospital discharge after cardiopulmonary arrest compared with children with surgical cardiac disease. Limited literature exists describing epidemiology and factors associated with mortality in this heterogeneous population. We aim to evaluate the clinical characteristics and outcomes after cardiopulmonary arrest in medical cardiac patients., Design: We performed a retrospective review of pediatric cardiac patients who underwent cardiopulmonary resuscitation in a tertiary care cardiac ICU. Surgical cardiac patients underwent cardiac surgery immediately prior to ICU admission. Nonsurgical cardiac patients were divided into two groups based on the presence of congenital heart disease: congenital heart disease medical or noncongenital heart disease medical. Clinical and outcome variables were collected. Primary outcome was survival to hospital discharge., Settings: Texas Children's Hospital cardiac ICU., Patients: Patients admitted to Texas Children's Hospital cardiac ICU between January 2011 and December 2016., Interventions: None., Measurements and Main Results: Of 150 cardiopulmonary arrest events reviewed, 90 index events were included (46 surgical, 26 congenital heart disease medical, and 18 noncongenital heart disease medical). There was no difference in primary outcome among the three groups. The absence of an epinephrine infusion precardiopulmonary arrest was associated with increased odds of survival in the congenital heart disease medical group (p = 0.03). Noncongenital heart disease medical patients experienced pulseless ventricular tachycardia/ventricular fibrillation more frequently than congenital heart disease medical patients (p = 0.02). Congenital heart disease medical patients had trends toward longer cardiac arrest durations, higher prevalence of neurologic sequelae postcardiopulmonary arrest, and higher mortality when extracorporeal support at cardiopulmonary resuscitation was employed., Conclusions: Although trends in first documented rhythm, neurologic sequelae, and inotropic support prior to cardiopulmonary arrest were noted between groups, no significant differences in survival after cardiac arrest were seen. Larger scale studies are needed to better describe factors associated with cardiopulmonary arrest as well as survival in heterogeneous medical cardiac populations.

Cardiac arrest occurs at a higher rate in children with heart disease than in healthy children. Pediatric basic life support and advanced life support guidelines focus on delivering high-quality resuscitation in children with normal hearts. The complexity and variability in pediatric heart disease pose unique challenges during resuscitation. A writing group appointed by the American Heart Association reviewed the literature addressing resuscitation in children with heart disease. MEDLINE and Google Scholar databases were searched from 1966 to 2015, cross-referencing pediatric heart disease with pertinent resuscitation search terms. The American College of Cardiology/American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. The recommendations in this statement concur with the critical components of the 2015 American Heart Association pediatric basic life support and pediatric advanced life support guidelines and are meant to serve as a resuscitation supplement. This statement is meant for caregivers of children with heart disease in the prehospital and in-hospital settings. Understanding the anatomy and physiology of the high-risk pediatric cardiac population will promote early recognition and treatment of decompensation to prevent cardiac arrest, increase survival from cardiac arrest by providing high-quality resuscitations, and improve outcomes with postresuscitation care., (© 2018 American Heart Association, Inc.)

Objective: We previously identified septic shock endotypes A and B based on 100 genes reflecting adaptive immunity and glucocorticoid receptor signaling. The endotypes differ with respect to outcome and corticosteroid responsiveness. We determined whether endotypes change during the initial 3 days of illness, and whether changes are associated with outcomes., Design: Observational cohort study including existing and newly enrolled participants., Setting: Multiple PICUs., Patients: Children with septic shock., Interventions: None., Measurements and Main Results: We measured the 100 endotyping genes at day 1 and day 3 of illness in 375 patients. We determined if endotype assignment changes over time, and whether changing endotype is associated with corticosteroid response and outcomes. We used multivariable logistic regression to adjust for illness severity, age, and comorbidity burden. Among the 132 subjects assigned to endotype A on day 1, 56 (42%) transitioned to endotype B by day 3. Among 243 subjects assigned to endotype B on day 1, 77 (32%) transitioned to endotype A by day 3. Assignment to endotype A on day 1 was associated with increased odds of mortality. This risk was modified by the subsequent day 3 endotype assignment. Corticosteroids were associated with increased risk of mortality among subjects who persisted as endotype A., Conclusions: A substantial proportion of children with septic shock transition endotypes during the acute phase of illness. The risk of poor outcome and the response to corticosteroids change with changes in endotype assignment. Patients persisting as endotype A are at highest risk of poor outcomes.

Objective: Hyperchloremia is associated with poor outcome among critically ill adults, but it is unknown if a similar association exists among critically ill children. We determined if hyperchloremia is associated with poor outcomes in children with septic shock., Design: Retrospective analysis of a pediatric septic shock database., Setting: Twenty-nine PICUs in the United States., Patients: Eight hundred ninety children 10 years and younger with septic shock., Interventions: None., Measurements and Main Results: We considered the minimum, maximum, and mean chloride values during the initial 7 days of septic shock for each study subject as separate hyperchloremia variables. Within each category, we considered hyperchloremia as a dichotomous variable defined as a serum concentration greater than or equal to 110 mmol/L. We used multivariable logistic regression to determine the association between the hyperchloremia variables and outcome, adjusted for illness severity. We considered all cause 28-day mortality and complicated course as the primary outcome variables. Complicated course was defined as mortality by 28 days or persistence of greater than or equal to two organ failures at day 7 of septic shock. Secondarily, we conducted a stratified analysis using a biomarker-based mortality risk stratification tool. There were 226 patients (25%) with a complicated course and 93 mortalities (10%). Seventy patients had a minimum chloride greater than or equal to 110 mmol/L, 179 had a mean chloride greater than or equal to 110 mmol/L, and 514 had a maximum chloride greater than or equal to 110 mmol/L. A minimum chloride greater than or equal to 110 mmol/L was associated with increased odds of complicated course (odds ratio, 1.9; 95% CI, 1.1-3.2; p = 0.023) and mortality (odds ratio, 3.7; 95% CI, 2.0-6.8; p < 0.001). A mean chloride greater than or equal to 110 mmol/L was also associated with increased odds of mortality (odds ratio, 2.1; 95% CI, 1.3-3.5; p = 0.002). The secondary analysis yielded similar results., Conclusion: Hyperchloremia is independently associated with poor outcomes among children with septic shock.

Objectives: Although clinical and pharmacologic guidelines exist for the practice of cardiopulmonary resuscitation in children (Pediatric Advanced Life Support), the practice of extracorporeal cardiopulmonary resuscitation in pediatric cardiac patients remains without universally accepted standards. We aim to explore variation in extracorporeal cardiopulmonary resuscitation procedures by surveying clinicians who care for this high-risk patient population., Design: A 28-item cross-sectional survey was distributed via a web-based platform to clinicians focusing on cardiopulmonary resuscitation practices and extracorporeal membrane oxygenation team dynamics immediately prior to extracorporeal membrane oxygenation cannulation., Settings: Pediatric hospitals providing extracorporeal mechanical support services to patients with congenital and/or acquired heart disease., Subjects: Critical care/cardiology specialist physicians, cardiothoracic surgeons, advanced practice nurse practitioners, respiratory therapists, and extracorporeal membrane oxygenation specialists., Interventions: None., Measurements and Main Results: Survey web links were distributed over a 2-month period with critical care and/or cardiology physicians comprising the majority of respondents (75%). Nearly all respondents practice at academic/teaching institutions (97%), 89% were from U.S./Canadian institutions and 56% reported less than 10 years of clinical experience. During extracorporeal cardiopulmonary resuscitation, a majority of respondents reported adherence to guideline recommendations for epinephrine bolus dosing (64%). Conversely, 19% reported using only one to three epinephrine bolus doses regardless of extracorporeal cardiopulmonary resuscitation duration. Inotropic support is held after extracorporeal membrane oxygenation cannulation "most of the time" by 58% of respondents and 94% report using afterload reducing/antihypertensive agents "some" to "most of the time" after achieving full extracorporeal membrane oxygenation support. Interruptions in chest compressions are common during active cannulation according to 77% of respondents., Conclusions: The results of this survey identify wide variability in resuscitative practices during extracorporeal cardiopulmonary resuscitation in the pediatric cardiac population. The deviations from established Pediatric Advanced Life Support CPR guidelines support a call for further inquiry into the pharmacologic and logistical care surrounding extracorporeal cardiopulmonary resuscitation.

Objective: We studied rapid response events after acute clinical instability outside ICU settings in pediatric cardiac patients. Our objective was to describe the characteristics and outcomes after rapid response events in this high-risk cohort and elucidate the cardiac conditions and risk factors associated with worse outcomes., Design: A retrospective single-center study was carried out over a 3-year period from July 2011 to June 2014., Setting: Referral high-volume pediatric cardiac center located within a tertiary academic pediatric hospital., Patients: All rapid response events that occurred during the study period were reviewed to identify rapid response events in cardiac patients., Interventions: None., Measurements and Main Results: We reviewed 1,906 rapid response events to identify 152 rapid response events that occurred in 127 pediatric cardiac patients. Congenital heart disease was the baseline diagnosis in 74% events (single ventricle, 28%; biventricle physiology, 46%). Seventy-four percent had a cardiac surgery before rapid response, 37% had ICU stay within previous 7 days, and acute kidney injury was noted in 41% post rapid response. Cardiac and/or pulmonary arrest occurred during rapid response in 8.5%. Overall, 81% were transferred to ICU, 22% had critical deterioration (ventilation or vasopressors within 12 hr of transfer), and 56% received such support and/or invasive procedures within 72 hours. Mortality within 30 days post event was 14%. Significant outcome associations included: single ventricle physiology-increased need for invasive procedures and mortality (adjusted odds ratio, 2.58; p = 0.02); multiple rapid response triggers-increased ICU transfer and interventions at 72 hours; critical deterioration-cardiopulmonary arrest and mortality; and acute kidney injury-cardiopulmonary arrest and need for hemodynamic support., Conclusions: Congenital heart disease, previous cardiac surgery, and recent discharge from ICU were common among pediatric cardiac rapid responses. Progression to cardiopulmonary arrest during rapid response, need for ICU care, kidney injury after rapid response, and mortality were high. Single ventricle physiology was independently associated with increased mortality.

Objective: Polymorphisms of the glucocorticoid receptor gene are associated with outcome and corticosteroid responsiveness among patients with inflammatory disorders. We conducted a candidate gene association study to test the hypothesis that these polymorphisms are associated with outcome and corticosteroid responsiveness among children with septic shock., Design: We genotyped 482 children with septic shock for the presence of two glucocorticoid receptor polymorphisms (rs56149945 and rs41423247) associated with increased sensitivity and one glucocorticoid receptor polymorphism (rs6198) associated with decreased sensitivity to corticosteroids. The primary outcome variable was complicated course, defined as 28-day mortality or the persistence of two or more organ failures 7 days after a septic shock diagnosis. We used logistic regression to test for an association between corticosteroid exposure and outcome, within genotype group, and adjusted for illness severity., Setting: Multiple PICUs in the United States., Interventions: Standard care., Measurements and Main Results: There were no differences in outcome when comparing the various genotype groups. Among patients homozygous for the wild-type glucocorticoid receptor allele, corticosteroids were independently associated with increased odds of complicated course (odds ratio, 2.30; 95% CI, 1.01-5.21; p = 0.047)., Conclusions: Based on these glucocorticoid receptor polymorphisms, we could not detect a beneficial effect of corticosteroids among any genotype group. Among children homozygous for the wild-type allele, corticosteroids were independently associated with increased odds of poor outcome.

Objective: To describe a number of the conditions associated with multiple organ dysfunction syndrome presented as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development multiple organ dysfunction syndrome workshop (March 26-27, 2015)., Data Sources: Literature review, research data, and expert opinion., Study Selection: Not applicable., Data Extraction: Moderated by an expert from the field, issues relevant to the association of multiple organ dysfunction syndrome with a variety of conditions were presented, discussed, and debated with a focus on identifying knowledge gaps and research priorities., Data Synthesis: Summary of presentations and discussion supported and supplemented by the relevant literature., Conclusions: There is a wide range of medical conditions associated with multiple organ dysfunction syndrome in children. Traditionally, sepsis and trauma are the two conditions most commonly associated with multiple organ dysfunction syndrome both in children and adults. However, there are a number of other pathophysiologic processes that may result in multiple organ dysfunction syndrome. In this article, we discuss conditions such as cancer, congenital heart disease, and acute respiratory distress syndrome. In addition, the relationship between multiple organ dysfunction syndrome and clinical therapies such as hematopoietic stem cell transplantation and cardiopulmonary bypass is also considered. The purpose of this article is to describe the association of multiple organ dysfunction syndrome with a variety of conditions in an attempt to identify similarities, differences, and opportunities for therapeutic intervention.

Objective: We evaluated the use of nesiritide in children with critical congenital heart disease, pulmonary congestion, and inadequate urine output despite conventional diuretic therapy., Design: We conducted a retrospective analysis of 26 consecutive patients, comprising 37 infusions occurring during separate hospitalizations. Hemodynamic variables, urine output, and serum creatinine levels were monitored prior to and throughout the duration of therapy with nesiritide. In addition, the stage of acute kidney injury was determined prior to and throughout the duration of the therapy using a standardized definition of acute kidney injury-The Kidney Disease: Improving Global Outcomes criteria., Setting: Cardiac ICU., Patients: Pediatric patients with critical congenital heart disease, pulmonary congestion, and inadequate urinary output despite diuretic therapy., Intervention: Nesiritide infusion., Measurements and Main Results: The use of nesiritide was associated with a significant decrease in the central venous pressure and heart rate with a trend toward a significant increase in urine output. During the course of therapy with nesiritide, the serum creatinine and stage of acute kidney injury decreased significantly. The decrease in stage of acute kidney injury became significant by day 4 (p = 0.006) and became more significant with time (last day of therapy compared with baseline; p < 0.001). During 12 of the 37 infusions, the stage of acute kidney injury decreased by two or more (p < 0.001)., Conclusions: Nesiritide had a favorable impact on hemodynamics and urine output in children with critical congenital heart disease and pulmonary congestion, and there was no worsening of renal function.

Objective: The Pediatric Sepsis Biomarker Risk Model (PERSEVERE), a pediatric sepsis risk model, uses biomarkers to estimate baseline mortality risk for pediatric septic shock. It is unknown how PERSEVERE performs within distinct septic shock phenotypes. We tested PERSEVERE in children with septic shock and thrombocytopenia-associated multiple organ failure (TAMOF), and in those without new onset thrombocytopenia but with multiple organ failure (MOF)., Design: PERSEVERE-based mortality risk was generated for each study subject (n = 660). A priori, we determined that if PERSEVERE did not perform well in both the TAMOF and the MOF cohorts, we would revise PERSEVERE to incorporate admission platelet counts., Setting: Multiple PICUs in the United States., Interventions: Standard care., Measurements and Main Results: PERSEVERE performed well in the TAMOF cohort (areas under the receiver operating characteristic curves [AUC], 0.84 [95% CI, 0.77-0.90]), but less well in the MOF cohort (AUC, 0.71 [0.61-0.80]). PERSEVERE was revised using 424 subjects previously reported in the derivation phase. PERSEVERE-II had an AUC of 0.89 (0.85-0.93) and performed equally well across TAMOF and MOF cohorts. PERSEVERE-II performed well when tested in 236 newly enrolled subjects. Sample size calculations for a clinical trial testing the efficacy of plasma exchange for children with septic shock and TAMOF indicated PERSEVERE-II-based stratification could substantially reduce the number of patients necessary, when compared with no stratification., Conclusions: Testing PERSEVERE in the context of septic shock phenotypes prompted a revision incorporating platelet count. PERSEVERE-II performs well upon testing, independent of TAMOF or MOF status. PERSEVERE-II could potentially serve as a prognostic enrichment tool., Competing Interests: AUTHOR COMPETING INTERESTS Dr. Wong and the Cincinnati Children’s Hospital Research Foundation have submitted a provisional patent application for PERSEVERE. Dr. Lindsell is named as a co-inventor in the above patent application. The other authors have no competing interests to report.

Objectives: Prognostic and predictive enrichment strategies are fundamental tools of precision medicine. Identifying children with septic shock who may benefit from corticosteroids remains a challenge. We combined prognostic and predictive strategies to identify a pediatric septic shock subgroup responsive to corticosteroids., Design: We conducted a secondary analysis of 288 previously published pediatric subjects with septic shock. For prognostic enrichment, each study subject was assigned a baseline mortality probability using the pediatric sepsis biomarker risk model. For predictive enrichment, each study subject was allocated to one of two septic shock endotypes, based on a 100-gene signature reflecting adaptive immunity and glucocorticoid receptor signaling. The primary study endpoint was complicated course, defined as the persistence of two or more organ failures at day 7 of septic shock or 28-day mortality. We used logistic regression to test for an association between corticosteroids and complicated course within endotype., Measurements and Main Results: Among endotype B subjects at intermediate to high pediatric sepsis biomarker risk model-based risk of mortality, corticosteroids were independently associated with more than a 10-fold reduction in the risk of a complicated course (relative risk, 0.09; 95% CI, 0.01-0.54; p = 0.007)., Conclusions: A combination of prognostic and predictive strategies based on serum protein and messenger RNA biomarkers can identify a subgroup of children with septic shock who may be more likely to benefit from corticosteroids. Prospective validation of these strategies and the existence of this subgroup are warranted., Competing Interests: The remaining authors have disclosed that they do not have any potential conflicts of interest.

Objectives: To identify a pediatric ventilator-associated condition definition for use in neonates and children by exploring whether potential ventilator-associated condition definitions identify patients with worse outcomes., Design: Retrospective cohort study and a matched cohort analysis., Setting: Pediatric, cardiac, and neonatal ICUs in five U.S. hospitals., Patients: Children 18 years old or younger ventilated for at least 1 day., Interventions: None., Measurements and Main Results: We evaluated the evidence of worsening oxygenation via a range of thresholds for increases in daily minimum fraction of inspired oxygen (by 0.20, 0.25, and 0.30) and daily minimum mean airway pressure (by 4, 5, 6, and 7 cm H2O). We required worsening oxygenation be sustained for at least 2 days after at least 2 days of stability. We matched patients with a ventilator-associated condition to those without and used Cox proportional hazard models with frailties to examine associations with hospital mortality, hospital and ICU length of stay, and duration of ventilation. The cohort included 8,862 children with 10,209 hospitalizations and 77,751 ventilator days. For the fraction of inspired oxygen 0.25/mean airway pressure 4 definition (i.e., increase in minimum daily fraction of inspired oxygen by 0.25 or mean airway pressure by 4), rates ranged from 2.9 to 3.2 per 1,000 ventilator days depending on ICU type; the fraction of inspired oxygen 0.30/mean airway pressure 7 definition yielded ventilator-associated condition rates of 1.1-1.3 per 1,000 ventilator days. All definitions were significantly associated with greater risk of hospital death, with hazard ratios ranging from 1.6 (95% CI, 0.7-3.4) to 6.8 (2.9-16.0), depending on thresholds and ICU type. Each definition was associated with prolonged hospitalization, time in ICU, and duration of ventilation, among survivors. The advisory board of the study proposed using the fraction of inspired oxygen 0.25/mean airway pressure 4 thresholds to identify pediatric ventilator-associated conditions in ICUs., Conclusions: Pediatric patients with ventilator-associated conditions are at substantially higher risk for mortality and morbidity across ICUs, regardless of thresholds used. Next steps include identification of risk factors, etiologies, and preventative measures for pediatric ventilator-associated conditions.

Objective: The development of acute kidney injury in patients with sepsis is associated with worse outcomes. Identifying those at risk for septic acute kidney injury could help to inform clinical decision making. We derived and tested a multibiomarker-based model to estimate the risk of septic acute kidney injury in children with septic shock., Design: Candidate serum protein septic acute kidney injury biomarkers were identified from previous transcriptomic studies. Model derivation involved measuring these biomarkers in serum samples from 241 subjects with septic shock obtained during the first 24 hours of admission and then using a Classification and Regression Tree approach to estimate the probability of septic acute kidney injury 3 days after the onset of septic shock, defined as at least two-fold increase from baseline serum creatinine. The model was then tested in a separate cohort of 200 subjects., Setting: Multiple PICUs in the United States., Interventions: None other than standard care., Measurements and Main Results: The decision tree included a first-level decision node based on day 1 septic acute kidney injury status and five subsequent biomarker-based decision nodes. The area under the curve for the tree was 0.95 (CI95, 0.91-0.99), with a sensitivity of 93% and a specificity of 88%. The tree was superior to day 1 septic acute kidney injury status alone for estimating day 3 septic acute kidney injury risk. In the test cohort, the tree had an area under the curve of 0.83 (0.72-0.95), with a sensitivity of 85% and a specificity of 77% and was also superior to day 1 septic acute kidney injury status alone for estimating day 3 septic acute kidney injury risk., Conclusions: We have derived and tested a model to estimate the risk of septic acute kidney injury on day 3 of septic shock using a novel panel of biomarkers. The model had very good performance in a test cohort and has test characteristics supporting clinical utility and further prospective evaluation.

Objectives: The postoperative cortisol profile and its association with early outcomes are poorly understood in neonates undergoing surgery for complex congenital heart disease. We investigated the postoperative profile of cortisol and its relationship with the clinical course in a cohort of newborns after stage-1 palliation for hypoplastic left heart syndrome., Design: Prospective observational study., Setting: Pediatric cardiovascular ICU at a tertiary children's hospital., Subjects: Twenty-three neonates after stage-1 palliation for hypoplastic left heart syndrome between 2009 and 2011., Interventions: None., Measurements and Main Results: Three serial measurements of total serum cortisol after surgery. The first measurement was taken immediately after surgery and the second and third-on the first and second postoperative mornings. The median weight of the infants was 3.0 kg (2.7-3.4 kg), and the age at surgery was 7 days (6-9 d). The median (25th-75th percentile) cortisol levels at admission, day 1, and day 2 were 96.2 μg/dL (51.1-112 μg/dL), 17.3 μg/dL (9.7-25.1 μg/dL), and 10 μg/dL (6.5-17 μg/dL), respectively (p < 0.0001 between admission and day 1). Higher cortisol was associated with greater morbidity, including the need for preoperative ventilation, increased total duration of ventilation, duration of inotropic support, and hospital length of stay., Conclusions: Cortisol levels fell significantly over the first 24 hours after stage-1 palliation for hypoplastic left heart syndrome. A higher postoperative cortisol was associated with increased postoperative morbidity, which warrants further investigation.

Objective: Observed associations between fluid balance and septic shock outcomes are likely confounded by initial mortality risk. We conducted a risk-stratified analysis of the association between post-ICU admission fluid balance and pediatric septic shock outcomes., Design: Retrospective analysis of an ongoing multicenter pediatric septic shock clinical and biological database., Setting: Seventeen PICUs in the United States., Patients: Three hundred and seventeen children with septic shock., Interventions: None., Measurements and Main Results: We stratified subjects into three mortality risk categories (low, intermediate, and high) using a validated biomarker-based stratification tool. Within each category, we assessed three fluid balance variables: total fluid intake/kg/d during the first 24 hours, percent positive fluid balance during the first 24 hours, and cumulative percent positive fluid balance up to 7 days. We used logistic regression to estimate the effect of fluid balance on the odds of 28-day mortality, and on complicated course, which we defined as either death within 28 days or persistence of two or more organ failures at 7 days. There were 40 deaths, and 91 subjects had a complicated course. Increased cumulative percent positive fluid balance was associated with mortality in the low-risk cohort (n = 204; odds ratio, 1.035; 95% CI, 1.004-1.066) but not in the intermediate- and high-risk cohorts. No other associations with mortality were observed. Fluid intake, percent positive fluid balance in the first 24 hours, and cumulative percent positive fluid balance were all associated with increased odds of a complicated course in the low-risk cohort but not in the intermediate- and high-risk cohorts., Conclusions: When stratified for mortality risk, increased fluid intake and positive fluid balance after ICU admission are associated with worse outcomes in pediatric septic shock patients with a low initial mortality risk but not in patients at moderate or high mortality risk.

Partial mechanical support devices are capable of partially unloading only one ventricle, often the systemic one, in the setting of acute circulatory failure. They are rarely used in the pediatric population, as the mode of circulatory failure in patients with congenital heart disease often involves biventricular or a predominantly right ventricular component. The devices include intra-aortic balloon pumping, Impella, TandemHeart, and CentriMag. They are rarely used as a bridge-to-recovery, but more often as a bridge-to-decision, or bridge-to-conversion to full mechanical support systems, such as extracorporeal membrane oxygenation or ventricular assist devices. Currently, lack of availability of more complete support devices, cost issues, or lack of infrastructure and personnel may still be indications to continue using partial mechanical support as opposed to more complete forms of biventricular circulatory support.

Objective: Septic shock heterogeneity has important implications for clinical trial implementation and patient management. We previously addressed this heterogeneity by identifying three putative subclasses of children with septic shock based exclusively on a 100-gene expression signature. Here we attempted to prospectively validate the existence of these gene expression-based subclasses in a validation cohort., Design: Prospective observational study involving microarray-based bioinformatics., Setting: Multiple pediatric intensive care units in the United States., Patients: Separate derivation (n = 98) and validation (n = 82) cohorts of children with septic shock., Interventions: None other than standard care., Measurements and Main Results: Gene expression mosaics of the 100 class-defining genes were generated for 82 individual patients in the validation cohort. Using computer-based image analysis, patients were classified into one of three subclasses ("A," "B," or "C") based on color and pattern similarity relative to reference mosaics generated from the original derivation cohort. After subclassification, the clinical database was mined for phenotyping. Subclass A patients had higher illness severity relative to subclasses B and C as measured by maximal organ failure, fewer intensive care unit-free days, and a higher Pediatric Risk of Mortality score. Patients in subclass A were characterized by repression of genes corresponding to adaptive immunity and glucocorticoid receptor signaling. Separate subclass assignments were conducted by 21 individual clinicians using visual inspection. The consensus classification of the clinicians had modest agreement with the computer algorithm., Conclusions: We have validated the existence of subclasses of children with septic shock based on a biologically relevant, 100-gene expression signature. The subclasses have relevant clinical differences.

Objectives: A systematic literature review and meta-analysis was performed to evaluate the impact of prophylaxis with palivizumab on mortality and morbidity associated with respiratory syncytial virus infection in infants at high risk (≤ 35 wks of gestational age, chronic lung disease, or congenital heart disease)., Data Sources: MEDLINE, EMBASE, and Current Contents were used. MEDLINE was searched from January 1, 1990 to May 16, 2007. The bibliographies of accepted studies and recent reviews and proceedings from the past 2 yrs were searched to identify additional relevant studies., Study Selection: Randomized controlled trials and prospective or retrospective cohort studies evaluating all-cause and respiratory syncytial virus-specific mortality, respiratory syncytial virus hospitalizations, and health care use in infants at high risk for respiratory syncytial virus infection receiving prophylaxis with palivizumab., Data Extraction: Data elements from each accepted study were extracted by one researcher and confirmed by a second researcher. Differences were resolved before data entry and analysis., Data Synthesis: A total of 2473 citations were screened and ten comparative studies of palivizumab prophylaxis evaluating >15,000 infants were included. Comparisons of mortality and hospitalization outcomes between infant groups using prophylaxis and not using prophylaxis were made using meta-analyses., Conclusions: Prophylaxis and nonprophylaxis infant groups appeared to be comparable at baseline. All-cause mortality during the respiratory syncytial virus season was 12 of 6380 (0.19%) for infants with prophylaxis vs. 33 of 8182 (0.53%) for infants without prophylaxis (Peto odds ratio, 0.30; 95% confidence interval, 0.17-0.55). Only five respiratory syncytial virus-specific deaths were reported, and the majority of the studies did not report respiratory syncytial virus-related deaths. The rate of respiratory syncytial virus hospitalization was significantly lower among preterm infants with prophylaxis compared with those without prophylaxis (4.1% vs. 10.4%; odds ratio, 0.35; 95% confidence interval, 0.25-0.47). Prophylaxis with palivizumab was associated with a reduction in all-cause mortality and respiratory syncytial virus hospitalization among preterm infants at high risk. Additional research on cause of death among infants at high risk is needed.

Serum biomarkers, such as B-type natriuretic peptide and troponin, are frequently measured in the cardiac intensive care unit. A review of the evidence supporting monitoring of these biomarkers is presented., Design: A search of MEDLINE, PubMed, and the Cochrane Database was conducted to find literature regarding the use of B-type natriuretic peptide and troponin in the cardiac intensive care setting. Adult and pediatric data were considered., Results and Conclusion: Both B-type natriuretic peptide and troponin have demonstrated utility in the intensive care setting but there is no conclusive evidence at this time that either biomarker can be used to guide inpatient management of children with cardiac disease. Although B-type natriuretic peptide and troponin concentrations can alert clinicians to myocardial stress, injury, or hemodynamic alterations, the levels can also be elevated in a variety of clinical scenarios, including sepsis. Observational studies have demonstrated that perioperative measurement of these biomarkers can predict postoperative mortality and complications., Recommendation and Level of Evidence: (class IIb, level of evidence B): The use of B-type natriuretic peptide and/or troponin measurements in the evaluation of hemodynamics and postoperative outcome in pediatric cardiac patients may be beneficial.