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Objectives: The goal of this study was to determine the incidence, prognostic performance, and generalizability of the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) organ dysfunction criteria using electronic health record (EHR) data. Additionally, we sought to compare the performance of the PODIUM criteria with the organ dysfunction criteria proposed by the 2005 International Pediatric Sepsis Consensus Conference (IPSCC)., Methods: Retrospective observational cohort study of critically ill children at 2 medical centers in the United States between 2010 and 2018. We assessed prevalence of organ dysfunction based on the PODIUM and IPSCC criteria for each 24-hour period from admission to 28 days. We studied the prognostic performance of the criteria to discriminate in-hospital mortality., Results: Overall, 22 427 PICU admissions met inclusion criteria, and in-hospital mortality was 2.3%. The cumulative incidence of each PODIUM organ dysfunction ranged from 15% to 30%, with an in-hospital mortality of 6% to 10% for most organ systems. The number of concurrent PODIUM organ dysfunctions demonstrated good-to-excellent discrimination for in-hospital mortality (area under the curve 0.87-0.93 for day 1 through 28) and compared favorably to the IPSCC criteria (area under the curve 0.84-0.92, P < .001 to P = .06)., Conclusions: We present the first evaluation of the PODIUM organ dysfunction criteria in 2 EHR databases. The use of the PODIUM organ dysfunction criteria appears promising for epidemiologic and clinical research studies using EHR data. More studies are needed to evaluate the PODIUM criteria that are not routinely collected in structured format in EHR databases., Competing Interests: FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

INTRODUCTIONThe clinical course of coronavirus 2019 (COVID-19) is heterogeneous, ranging from mild to severe multiorgan failure and death. In this study, we analyzed cell-free DNA (cfDNA) as a biomarker of injury to define the sources of tissue injury that contribute to such different trajectories.METHODSWe conducted a multicenter prospective cohort study to enroll patients with COVID-19 and collect plasma samples. Plasma cfDNA was subject to bisulfite sequencing. A library of tissue-specific DNA methylation signatures was used to analyze sequence reads to quantitate cfDNA from different tissue types. We then determined the correlation of tissue-specific cfDNA measures to COVID-19 outcomes. Similar analyses were performed for healthy controls and a comparator group of patients with respiratory syncytial virus and influenza.RESULTSWe found markedly elevated levels and divergent tissue sources of cfDNA in COVID-19 patients compared with patients who had influenza and/or respiratory syncytial virus and with healthy controls. The major sources of cfDNA in COVID-19 were hematopoietic cells, vascular endothelium, hepatocytes, adipocytes, kidney, heart, and lung. cfDNA levels positively correlated with COVID-19 disease severity, C-reactive protein, and D-dimer. cfDNA profile at admission identified patients who subsequently required intensive care or died during hospitalization. Furthermore, the increased cfDNA in COVID-19 patients generated excessive mitochondrial ROS (mtROS) in renal tubular cells in a concentration-dependent manner. This mtROS production was inhibited by a TLR9-specific antagonist.CONCLUSIONcfDNA maps tissue injury that predicts COVID-19 outcomes and may mechanistically propagate COVID-19-induced tissue injury.FUNDINGIntramural Targeted Anti-COVID-19 grant, NIH.

Objectives: To describe changes in the occurrence of restricting symptoms at the end of life from 1998 to 2019 and compare these changes according to the condition leading to death., Design: Prospective longitudinal study., Setting: Greater New Haven, CT., Participants: A total of 665 decedents from a cohort of 754 community-living persons, 70 years or older., Measurements: The occurrence of 16 restricting symptoms was ascertained during monthly interviews. Information on the conditions leading to death was obtained from death certificates and comprehensive assessments that were completed every 18-months. For each restricting symptom, adjusted rates (per 100 person-months) were calculated separately for six multiyear time intervals., Results: From 1998 to 2019, rates decreased for five (31.3%) restricting symptoms (difficulty sleeping; chest pain or tightness; shortness of breath; cold or flu symptoms; and nausea, vomiting, or diarrhea), increased for three (18.8%: arm or leg weakness; urinary incontinence; and memory or thinking problem), and changed little for the other eight (50.0%: poor eyesight; anxiety; depression; musculoskeletal pain; fatigue; dizziness or unsteadiness; frequent or painful urination; and swelling in feet or ankles). The decrease in rates was most pronounced for shortness of breath, with a reduction from 15.0 (95% credible interval = 11.7-18.6) in 1998 to 2001 to 8.2 (95% credible interval = 5.9-10.5) in 2014 to 2019, yielding a rate ratio (95% credible interval) of 0.92 (0.86-0.98). When evaluated according to the condition leading to death, the results were similar, with 10 of the 13 statistically significant rate ratios representing decreases in rates over time and only 3 representing increases., Conclusion: The occurrence of most restricting symptoms at the end of life has been decreasing or stable over the past two decades. These results suggest that end-of-life care has been improving, although additional efforts will be needed to further reduce symptom burden at the end of life., (© 2020 The American Geriatrics Society.)

Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe diffuse cardiac inflammation often leading to death resulting from cardiogenic shock, ventricular arrhythmias, or multiorgan system failure. Historically, FM was almost exclusively diagnosed at autopsy. By definition, all patients with FM will need some form of inotropic or mechanical circulatory support to maintain end-organ perfusion until transplantation or recovery. Specific subtypes of FM may respond to immunomodulatory therapy in addition to guideline-directed medical care. Despite the increasing availability of circulatory support, orthotopic heart transplantation, and disease-specific treatments, patients with FM experience significant morbidity and mortality as a result of a delay in diagnosis and initiation of circulatory support and lack of appropriately trained specialists to manage the condition. This scientific statement outlines the resources necessary to manage the spectrum of FM, including extracorporeal life support, percutaneous and durable ventricular assist devices, transplantation capabilities, and specialists in advanced heart failure, cardiothoracic surgery, cardiac pathology, immunology, and infectious disease. Education of frontline providers who are most likely to encounter FM first is essential to increase timely access to appropriately resourced facilities, to prevent multiorgan system failure, and to tailor disease-specific therapy as early as possible in the disease process.

Background: Despite advancements in treatment and survival, pediatric organ failure and transplant populations continue to face significant risks of morbidity and mortality. Little scientific attention has been given to addressing the end-of-life care needs of this growing population of young people. This study characterized current practices, beliefs, and challenges specific to the disclosure of prognosis and end-of-life care topics among providers caring for pediatric organ failure and transplant populations., Methods: This cross-sectional study included 144 healthcare providers actively caring for children, adolescents, and young adults with organ failure or solid organ transplant history. Participants completed an electronic survey measuring frequency and comfort in discussing the following topics with patients and parents: prognosis/survival statistics, re-transplantation, advance care planning (ACP), and death/dying. Descriptive statistics, two-sample t tests, and analysis of variance were used., Results: Fewer than half of respondents regularly discuss prognosis/survival statistics and potential need for re-transplantation with their pediatric and young adult patients. Less than 20% of providers engage their pediatric patients in ACP discussions, and approximately 30% facilitate such discussions with young adult patients. Pediatric organ failure and transplant providers endorse a number of barriers specific to discussing these topics., Conclusion: Pediatric organ failure and transplant providers do not regularly discuss prognosis or end-of-life care topics with this patient population. Communication-focused intervention research is needed to improve honest and compassionate discussion of these topics that is aligned with both patients' and parents' needs and preferences., (© 2019 Wiley Periodicals, Inc.)

Background: There are limited data on acute noncardiac multiorgan failure in cardiogenic shock complicating acute myocardial infarction (AMI-CS)., Objectives: The authors sought to evaluate the 15-year national trends, resource utilization, and outcomes of single and multiple noncardiac organ failures in AMI-CS., Methods: This was a retrospective cohort study of AMI-CS using the National Inpatient Sample database from 2000 to 2014. Previously validated codes for respiratory, renal, hepatic, hematologic, and neurological failure were used to identify single or multiorgan (≥2 organ systems) noncardiac organ failure. Outcomes of interest were in-hospital mortality, temporal trends, and resource utilization. The effects of every additional organ failure on in-hospital mortality and resource utilization were assessed., Results: In 444,253 AMI-CS admissions, noncardiac single or multiorgan failure was noted in 32.4% and 31.9%, respectively. Multiorgan failure was seen more commonly in admissions with non-ST-segment elevation AMI-CS, nonwhite race, and higher baseline comorbidity. There was a steady increase in the prevalence of single and multiorgan failure. Coronary angiography and revascularization were performed less commonly in multiorgan failure. Single-organ failure (odds ratio: 1.28; 95% confidence interval: 1.26 to 1.30) and multiorgan failure (odds ratio: 2.23; 95% confidence interval: 2.19 to 2.27) were independently associated with higher in-hospital mortality, greater resource utilization, and fewer discharges to home. There was a stepwise increase in in-hospital mortality and resource utilization with each additional organ failure., Conclusions: There has been a steady increase in the prevalence of multiorgan failure in AMI-CS. Presence of multiorgan failure was independently associated with higher in-hospital mortality and greater resource utilization., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Administrative claims data are commonly used for sepsis surveillance, research, and quality improvement. However, variations in diagnosis, documentation, and coding practices for sepsis and organ dysfunction may confound efforts to estimate sepsis rates, compare outcomes, and perform risk adjustment. We evaluated hospital variation in the sensitivity of claims data relative to clinical data from electronic health records and its impact on outcome comparisons., Design, Setting, and Patients: Retrospective cohort study of 4.3 million adult encounters at 193 U.S. hospitals in 2013-2014., Interventions: None., Measurements and Main Results: Sepsis was defined using electronic health record-derived clinical indicators of presumed infection (blood culture draws and antibiotic administrations) and concurrent organ dysfunction (vasopressors, mechanical ventilation, doubling in creatinine, doubling in bilirubin to ≥ 2.0 mg/dL, decrease in platelets to < 100 cells/µL, or lactate ≥ 2.0 mmol/L). We compared claims for sepsis prevalence and mortality rates between both methods. All estimates were reliability adjusted to account for random variation using hierarchical logistic regression modeling. The sensitivity of hospitals' claims data was low and variable: median 30% (range, 5-54%) for sepsis, 66% (range, 26-84%) for acute kidney injury, 39% (range, 16-60%) for thrombocytopenia, 36% (range, 29-44%) for hepatic injury, and 66% (range, 29-84%) for shock. Correlation between claims and clinical data was moderate for sepsis prevalence (Pearson coefficient, 0.64) and mortality (0.61). Among hospitals in the lowest sepsis mortality quartile by claims, 46% shifted to higher mortality quartiles using clinical data. Using implicit sepsis criteria based on infection and organ dysfunction codes also yielded major differences versus clinical data., Conclusions: Variation in the accuracy of claims data for identifying sepsis and organ dysfunction limits their use for comparing hospitals' sepsis rates and outcomes. Using objective clinical data may facilitate more meaningful hospital comparisons.

Background: The "Age of Blood in Children in Pediatric Intensive Care Unit" (ABC PICU) study is a randomized controlled trial (RCT) that aims to determine if red blood cell (RBC) unit storage age affects outcomes in critically ill children. While RBCs can be stored for up to 42 days in additive solutions, their efficacy and safety after long-term storage have been challenged. Preclinical and clinical observational evidence suggests loss of efficacy and lack of safety of older RBC units, especially in more vulnerable populations such as critically ill children. Because there is a belief that shorter storage will improve outcomes, some physicians and institutions systematically transfuse fresh RBCs to children. Conversely, the standard practice of blood banks is to deliver the oldest available RBC unit (first-in, first-out policy) in order to decrease wastage., Methods/design: The ABC PICU study, is a double-blind superiority trial comparing the development of "New or Progressive Multiple Organ Dysfunction Syndrome" (NPMODS) in 1538 critically ill children randomized to either transfusion with RBCs stored for ≤ 7 days or to standard-issue RBCs (oldest in inventory). Patients are being recruited from 52 centers in the US, Canada, France, Italy, and Israel., Discussion: The ABC PICU study should have significant implications for blood procurement services. A relative risk reduction of 33% is postulated in the short-storage arm. If a difference is found, this will indicate that fresher RBCs do improve outcomes in the pediatric intensive care unit population and would justify that use in critically ill children. If no difference is found, this will reassure clinicians and transfusion medicine specialists regarding the safety of the current system of allocating the oldest RBC unit in inventory and will discourage clinicians from preferentially requesting fresher blood for critically ill children., Trial Registration: ClinicalTrials.gov, ID: NCT01977547 . Registered on 6 November 2013.

Background: Severe sepsis is a common and costly problem. Although consistently defined clinically by consensus conference since 1991, there have been several different implementations of the severe sepsis definition using ICD-9-CM codes for research. We conducted a single center, patient-level validation of 1 common implementation of the severe sepsis definition, the so-called "Angus" implementation., Methods: Administrative claims for all hospitalizations for patients initially admitted to general medical services from an academic medical center in 2009-2010 were reviewed. On the basis of ICD-9-CM codes, hospitalizations were sampled for review by 3 internal medicine-trained hospitalists. Chart reviews were conducted with a structured instrument, and the gold standard was the hospitalists' summary clinical judgment on whether the patient had severe sepsis., Results: Three thousand one hundred forty-six (13.5%) hospitalizations met ICD-9-CM criteria for severe sepsis by the Angus implementation (Angus-positive) and 20,142 (86.5%) were Angus-negative. Chart reviews were performed for 92 randomly selected Angus-positive and 19 randomly-selected Angus-negative hospitalizations. Reviewers had a κ of 0.70. The Angus implementation's positive predictive value was 70.7% [95% confidence interval (CI): 51.2%, 90.5%]. The negative predictive value was 91.5% (95% CI: 79.0%, 100%). The sensitivity was 50.4% (95% CI: 14.8%, 85.7%). Specificity was 96.3% (95% CI: 92.4%, 100%). Two alternative ICD-9-CM implementations had high positive predictive values but sensitivities of <20%., Conclusions: The Angus implementation of the international consensus conference definition of severe sepsis offers a reasonable but imperfect approach to identifying patients with severe sepsis when compared with a gold standard of structured review of the medical chart by trained hospitalists.

Background: Although the identification and management of anaphylaxis in an emergency department setting has been well studied, our understanding of the risk factors for admission in a community-based hospital is lacking., Objective: To determine the demographics and the predictors of hospitalization, in patients presenting with anaphylaxis to a community-based emergency department (ED)., Methods: We performed a five-year retrospective chart review of all patients seen in the ED of Winthrop University Hospital, a community-based institution, with an International Classification of Diseases, 9(th)Edition code related to anaphylaxis., Results: Fifty-eight visits met inclusion criteria, of which 34% resulted in hospital admission (95% CI: 22-48%). Univariate predictors for admission included (1) the involvement of 2, 3, and 4 organ systems (26%, 55%, and 75%, respectively; P < .02); (2) gastrointestinal symptoms vs no symptoms (59% vs 24%, P < .02); (3) non-sting (ingested and other allergens) vs insect sting allergen (50% vs 12.5%, P < .005); and (4) a history of an ED visit for anaphylaxis vs none (67% vs 30%, P < .05). Multivariate analysis (logistic regression) confirmed non-sting allergens (p < 0.02) and number of organ systems involved (P < .05) as independent predictors of hospitalization., Conclusion: In our study population, the involvement of multiple organ systems, particularly gastrointestinal involvement, a history of ED visits for anaphylaxis, and involvement of ingested or other allergens (non-sting) demonstrated higher admission rates., (Copyright © 2012. Published by Elsevier Inc.)

Objective: The Sequential Organ Failure Assessment (SOFA) score has been recommended for triage during a mass influx of critically ill patients, but it requires laboratory measurement of 4 parameters, which may be impractical with constrained resources. We hypothesized that a modified SOFA (MSOFA) score that requires only 1 laboratory measurement would predict patient outcome as effectively as the SOFA score., Methods: After a retrospective derivation in a prospective observational study in a 24-bed medical, surgical, and trauma intensive care unit, we determined serial SOFA and MSOFA scores on all patients admitted during the 2008 calendar year and compared the ability to predict mortality and the need for mechanical ventilation., Results: A total of 1770 patients (56% male patients) with a 30-day mortality of 10.5% were included in the study. Day 1 SOFA and MSOFA scores performed equally well at predicting mortality with an area under the receiver operating curve (AUC) of 0.83 (95% confidence interval 0.81-.85) and 0.84 (95% confidence interval 0.82-.85), respectively (P = .33 for comparison). Day 3 SOFA and MSOFA predicted mortality for the 828 patients remaining in the intensive care unit with an AUC of 0.78 and 0.79, respectively. Day 5 scores performed less well at predicting mortality. Day 1 SOFA and MSOFA predicted the need for mechanical ventilation on day 3, with an AUC of 0.83 and 0.82, respectively. Mortality for the highest category of SOFA and MSOFA score (>11 points) was 53% and 58%, respectively., Conclusions: The MSOFA predicts mortality as well as the SOFA and is easier to implement in resource-constrained settings, but using either score as a triage tool would exclude many patients who would otherwise survive.

Objective: To determine chronic illness outcomes after admission with multiple organ dysfunction syndrome (MODS) for patients in the pediatric intensive care unit (PICU)., Study Design: We evaluated consecutive PICU admissions from 35 US children's hospitals from January 2004-December 2005 in the virtual PICU Performance System database. We excluded hospitals with >10% missing values for MODS variables and patients<1 month or>18 years of age. MODS was identified by laboratory and vital sign values from day of admission with International Pediatric Sepsis Consensus Conference criteria. Chronic illness was identified by secondary diagnoses, classified by modified Delphi method. We evaluated functional outcomes with pediatric overall performance category and pediatric cerebral performance category scores from PICU admission and discharge., Results: Of 44 693 admissions, 52.1% had a chronic diagnosis. Chronic diagnoses increased MODS at PICU admission (24.6% vs 12.0%, P<.001) and mortality rates (3.7% vs 1.9%, P<.001). Patients with a chronic diagnosis had similar changes in pediatric overall performance category and pediatric cerebral performance category scores from PICU admission to discharge as previously healthy children. However, outcome in different chronic diagnosis categories was variable., Conclusions: Chronic illness increased MODS incidence at PICU admission and impacted all-cause PICU mortality rates. Although, in aggregate, children who survive return to baseline functional status, this varies by chronic illness category., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Background: Revised consensus sepsis definitions have been published in 2003. The present study was performed to compare the prevalence of different stages of sepsis and ICU mortality rates and find out the case mix within the same collective of postoperative/posttraumatic patients applying either the original 1992 ACCP/SCCM or the revised 2003 SCCM/ESICM/ACCP/ATS/SIS sepsis definitions., Methods: Retrospective observational single-centre study in surgical critically ill patients admitted to an University adult ICU. From 01/2007 to 12/2007, 742 patients were surveyed daily computer-assisted with respect to different stages of sepsis., Results: Within the same patient collective, applying the 2003 definitions instead of the 1992 definitions, prevalence of severe sepsis (61 vs. 56) and septic shock (205 vs. 162) was higher (p < 0.001). In patients with septic shock according to the 2003 definitions, mortality rate of 22% was lower than that of 27%, when the 1992 definitions were used. Risk of death was increased for those patients classified to be in septic shock with any of the definitions (OR 6.5, p = 0.001). Sensitivity to predict deaths was slightly higher with the 2003 definitions (92%) than with the 1992 definitions (88%), and specificity was lower (31% vs. 49%)., Conclusion: The prevalence and mortality rates of various sepsis severity stages differ if defined by the 1992 or the 2003 definitions. Thus, transferring conclusions drawn from data sets regarding severity of sepsis generated with the 1992 definitions to the same population applying the 2003 definitions may be misleading. The 1992 definitions may under-classify patients with severe sepsis.

Objectives: To use measures of organ dysfunction derived from administrative data to assess clinical and economic outcomes in hospitalized children., Study Design: We used the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnostic and procedure codes to evaluate organ dysfunction in all patients, excluding neonates, in the Healthcare Cost and Utilization Project Kids' Inpatient Database (KID). We adapted consensus clinical definitions to characterize organ dysfunction in terms of degree of impairment, type of organ system involvement, and number of dysfunctional organ systems. Univariate and multivariable models were constructed to determine the impact of organ dysfunction on in-hospital mortality and resource use., Results: Patients with organ dysfunction (n=51,386) were younger and more often male than those without organ dysfunction, and they had significantly higher in-hospital mortality and resource use. Organ dysfunction, assessed in terms of degree, type, and number of dysfunctional organ systems, was consistently associated with all hospital outcomes. In multivariable models, types of organ system failures were most predictive of in-hospital mortality, whereas degree of organ system involvement allowed for a better assessment of resource use., Conclusions: Administrative data can be used to characterize multiple dimensions of organ dysfunction in children. Hospitalizations involving organ dysfunction are associated with significant clinical and economic consequences.

Objective: To review the epidemiology and pathophysiology of gram-negative sepsis and the new consensus terminology describing the clinical signs of sepsis., Data Sources: Review of the medical literature and compiled data from animal and clinical trials., Participants: Members of the Society of Critical Care Medicine, American College of Chest Physicians and American Association of Critical-Care Nurses with expertise on the subject of sepsis and its complications., Results: Preconference and general sessions were offered at the National Teaching Institutes of the American Association of Critical-Care Nurses, with the goal of clarifying the epidemiology, risk factors and pathophysiology of gram-negative sepsis. In addition, current terminology and new (1992) consensus terminology describing the clinical signs of sepsis were presented. Special emphasis was placed on the role of the healthcare provider in the prevention and recognition of sepsis and the role of the septic mediators in the septic cascade., Conclusions: If the incidence of sepsis is to be reduced, the healthcare provider must be aware of the risk factors for sepsis and methods of reducing nosocomial infections. A thorough understanding of the role of mediators and consensus terminology used to describe sepsis, severe sepsis, septic shock and multiple organ dysfunction syndrome is necessary to recognize early or progressive signs of sepsis and to initiate state-of-the-art therapy.