Life-Threatening Bleeding in Children: A Prospective Observational Study.

OBJECTIVES: The purpose of our study was to describe children with life-threatening bleeding. DESIGN: We conducted a prospective observational study of children with life-threatening bleeding events. SETTING: Twenty-four childrens hospitals in the United States, Canada, and Italy participated. SUBJECTS: Children 0-17 years old who received greater than 40 mL/kg total blood products over 6 hours or were transfused under massive transfusion protocol were included. INTERVENTIONS: Children were compared according bleeding etiology: trauma, operative, or medical. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, therapies administered, and clinical outcomes were analyzed. Among 449 enrolled children, 55.0% were male, and the median age was 7.3 years. Bleeding etiology was 46.1% trauma, 34.1% operative, and 19.8% medical. Prior to the life-threatening bleeding event, most had age-adjusted hypotension (61.2%), and 25% were hypothermic. Children with medical bleeding had higher median Pediatric Risk of Mortality scores (18) compared with children with trauma (11) and operative bleeding (12). Median Glasgow Coma Scale scores were lower for children with trauma (3) compared with operative (14) or medical bleeding (10.5). Median time from bleeding onset to first transfusion was 8 minutes for RBCs, 34 minutes for plasma, and 42 minutes for platelets. Postevent acute respiratory distress syndrome (20.3%) and acute kidney injury (18.5%) were common. Twenty-eight-day mortality was 37.5% and higher among children with medical bleeding (65.2%) compared with trauma (36.1%) and operative (23.8%). There were 82 hemorrhage deaths; 65.8% occurred by 6 hours and 86.5% by 24 hours. CONCLUSIONS: Patient characteristics and outcomes among children with life-threatening bleeding varied by cause of bleeding. Mortality was high, and death from hemorrhage in this population occurred rapidly.

Rapid Transition of a PICU Space and Staff to Adult Coronavirus Disease 2019 ICU Care.

OBJECTIVES: We describe the process by which a PICU and a PICU care team were incorporated into a hospital-wide ICU care model during the coronavirus disease 2019 pandemic. DESIGN: A descriptive, retrospective report from a single-center PICU. SETTING: Twenty-three bed, quaternary PICU, within an 862-bed hospital. PATIENTS: Critically ill adults, with coronavirus disease 2019-related disease. INTERVENTIONS: ICU care provided by pediatric intensivists with training and support from medical intensivists. MEASUREMENTS AND MAIN RESULTS: Within the context of the institution's comprehensive effort to centralize and systematize care for adults with severe coronavirus disease 2019 disease, the PICU was transitioned to an adult coronavirus disease 2019 critical care unit. Nurses and physicians underwent just-in-time training over 3 days and 2 weeks, respectively. Medical ICU physicians and nurses provided oversight for care and designated hospital-based teams were available for procedures and common adult emergencies. Over a 7-week period, the PICU cared for 60 adults with coronavirus disease 2019-related critical illness. Fifty-three required intubation and mechanical ventilation for a median of 18 days. Eighteen required renal replacement therapy and 17 died. CONCLUSIONS: During the current and potentially in future pandemics, where critical care resources are limited, pediatric intensivists and staff can be readily utilized to meaningfully contribute to the care of critically ill adults.

Critical Care for Coronavirus Disease 2019: Perspectives From the PICU to the Medical ICU.

OBJECTIVES: To describe the unique perspective of pediatric intensivists caring for critically ill adults during the coronavirus disease 2019 pandemic. DESIGN: Observational study. SETTING: Academic medical center in New York City. PATIENTS: Coronavirus disease 2019 positive adults requiring admission to an ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In late March 2020, New York Presbyterian Hospital centralized all of its inpatient pediatric units (n = 4) from across the network to a single center, in order to create space to accommodate the increasing number of critically ill adults with coronavirus disease 2019. Within 1 week, the PICU at New York Presbyterian Hospital-Weill Cornell Medicine transferred or discharged all inpatients, underwent a transformation of the physical space, and began admitting adults of all ages with coronavirus disease 2019 related acute respiratory failure. The New York Presbyterian Hospital-Weill Cornell Medicine PICU physician group continued to lead this unit. PICU nurses, respiratory therapists, social workers, and child life specialists joined their PICU physician colleagues to care for these critically ill adults. CONCLUSIONS: In the coronavirus disease 2019 pandemic, PICU physicians are well poised to care for adult patients in a surge capacity, and bring a unique perspective to the experience.

A call for transparent reporting to optimize the predictive value of preclinical research.

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.

NIH Music-Based Intervention Toolkit: Music-Based Interventions for Brain Disorders of Aging.

Music-based interventions (MBIs) show promise for managing symptoms of various brain disorders. To fully realize the potential of MBIs and dispel the outdated misconception that MBIs are rooted in soft science, the NIH is promoting rigorously designed, well-powered MBI clinical trials. The pressing need of guidelines for scientifically rigorous studies with enhanced data collection brought together the Renée Fleming Foundation, the Foundation for the NIH, the Trans-NIH Music and Health Working Group, and an interdisciplinary scientific expert panel to create the NIH MBI Toolkit for research on music and health across the lifespan. The Toolkit defines the building blocks of MBIs, including a consolidated set of common data elements for MBI protocols, and core datasets of outcome measures and biomarkers for brain disorders of aging that researchers may select for their studies. Utilization of the guiding principles in this Toolkit will be strongly recommended for NIH-funded studies of MBIs.

Development and testing of low-volume hyperoncotic, hyperosmotic spray-dried plasma for the treatment of trauma-associated coagulopathy.

BACKGROUND: Trauma-associated coagulopathy carries an extremely high mortality. Fresh-frozen plasma (FFP) is the mainstay of treatment; however, its availability in the battlefield is limited. We have already shown that lyophilized, freeze-dried plasma (FDP) reconstituted in its original volume can reverse trauma-associated coagulopathy. To enhance the logistical advantage (lower volume and weight), we developed and tested a hyperoncotic, hyperosmotic spray-dried plasma (SDP) product in a multiple injuries/hemorrhagic shock swine model. METHODS: Plasma separated from fresh porcine blood was stored as FFP or preserved as FDP and SDP. In in vitro testing, SDP was reconstituted in distilled water that was either equal (1 × SDP) or one-third (3 × SDP) the original volume of FFP. Analysis included measurements of prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen levels, and activity of selected clotting factors. In in vivo testing, swine were subjected to multiple injuries (femur fracture and grade V liver injury) and hemorrhagic shock (60% arterial hemorrhage, with the "lethal triad" of acidosis, coagulopathy, and hypothermia) and were treated with FFP, FDP, or 3 × SDP (n=4-5/group). Coagulation profiles (PT, PTT, and thromboelastography) were measured at baseline, post-shock, post-crystalloid, treatment (M0), and during 4 hours of monitoring (M1-4). RESULTS: In vitro testing revealed that clotting factors were preserved after spray drying. The coagulation profiles of FFP and 1 × SDP were similar, with 3 × SDP showing a prolonged PT/PTT. Multiple injuries/hemorrhagic shock produced significant coagulopathy, and 3 × SDP infusion was as effective as FFP and FDP in reversing it. CONCLUSION: Plasma can be spray dried and reconstituted to one-third of its original volume without compromising the coagulation properties in vivo. This shelf-stable, low-volume, hyperoncotic, hyperosmotic plasma is a logistically attractive option for the treatment of trauma-associated coagulopathy in austere environments, such as a battlefield.

Treatment with histone deacetylase inhibitor attenuates MAP kinase mediated liver injury in a lethal model of septic shock.

BACKGROUND: Despite global efforts to improve the treatment of sepsis, it remains a leading cause of morbidity and mortality in intensive care units. We have previously shown that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, markedly improves survival in a murine model of lipopolysaccharide (LPS)-induced shock. SAHA has anti-inflammatory properties that have not been fully characterized. The liver plays an important role in the production of acute phase reactants involved in the inflammatory cascade and is also one of the major organs that can become dysfunctional in septic shock. The purpose of this study was to assess the effect of SAHA treatment on MAP kinases and associated inflammatory markers in murine liver after LPS-induced injury. METHODS: C57B1/6J mice were randomly divided into three groups: (A) experimental-given intraperitoneal (i.p.) SAHA (50 mg/kg) in dimethyl sulfoxide (DMSO) vehicle solution (n = 12); (B) control- given vehicle only (n = 12), and; (C) sham-given no treatment (n = 7). Two hours later, experimental and control mice were injected with LPS (20 mg/kg, i.p.) and experimental mice received a second dose of SAHA. Livers were harvested at 3, 24, and 48 h for analysis of inflammatory markers using Western Blot, Polymerase Chain Reaction (PCR), and Enzyme-Linked Immunosorbent Assay (ELISA) techniques. RESULTS: After 3 h, the livers of animals treated with SAHA showed significantly (P < 0.05) decreased expression of the pro-inflammatory MAP kinases phosphorylated p38, phosphorylated ERK, myeloperoxidase and interleukin-6, and increased levels of the anti-inflammatory interleukin-10 compared with controls. Phospho-p38 expression remained low in the SAHA treated groups at 24 and 48 h. CONCLUSION: Administration of SAHA is associated with attenuation of MAPK activation and alteration of inflammatory and anti-inflammatory markers in murine liver after a lethal LPS insult. The suppression of MAPK activity is rapid (within 3 h), and is sustained for up to 48 h post-treatment. These results may in part account for the improvement in survival shown in this model.

Induced hypothermia for trauma: current research and practice.

Induction of hypothermia with the goal of providing therapeutic benefit has been accepted for use in the clinical setting of adult cardiac arrest and neonatal hypoxic-ischemic encephalopathy (HIE). However, its potential as a treatment in trauma is not as well defined. This review discusses potential benefits and complications of induced hypothermia (IH) with emphasis on the current state of knowledge and practice in various types of trauma. There is excellent preclinical research showing that in cases of penetrating trauma with cardiac arrest, inducing hypothermia to 10 degrees C using cardiopulmonary bypass (CPB) could possibly save those otherwise likely to die without causing neurologic sequelae. A human trial of this intervention is about to get underway. Preclinical studies suggest that inducing hypothermia may be useful to delay cardiac arrest in penetrating trauma victims who are hypotensive. There is potential for IH to be used in cases of blunt trauma, but it has not been well studied. In the case of traumatic brain injury (TBI), clinical trials have shown conflicting results, despite almost uniform efficacy seen in preclinical experiments. Major studies are analyzed and ways to standardize its use and optimize future clinical trials are discussed. More preclinical and clinical research is needed to better define whether there could be a role for IH in the case of spinal cord injuries.

Alterations in gene expression after induction of profound hypothermia for the treatment of lethal hemorrhage.

INTRODUCTION: We have previously demonstrated that induction of profound hypothermia improves long-term survival in animal models of complex injuries/lethal hemorrhage. However, the precise mechanisms have not been well defined. The aim of this high-throughput study was to investigate the impact of profound hypothermia on gene expression profiles. METHODS: Wistar-Kyoto rats underwent 40% blood volume arterial hemorrhage over 10 minutes and were randomized into two groups based on core body temperatures (n = 7 per group): hypothermia (H, 15 degrees C) and normothermia (N, 37 degrees C). Hypothermia was induced by infusing cold isotonic solution using a cardiopulmonary bypass (CPB) setup. After reaching target body temperature, low-flow state (CPB flow rate of 20 mL x kg x min) was maintained for 60 minutes. Hypothermic rats were rewarmed to baseline temperature, and all rats were resuscitated on CPB and monitored for 3 hours. The N group underwent identical CPB management. Sham rats (no hemorrhage and no instrumentation) were used as controls. Blood samples were collected serially, and hepatic tissues were harvested after 3 hours. Affymatrix Rat Gene 1.0 ST Array (27,342 genes, >700,000 probes) was used to determine gene expression profiles (n = 3 per group), which were further analyzed using GeneSpring (Agilent Technologies, Santa Clara, CA) and GenePattern (Broad Institute, Cambridge, MA) programs. Data were further queried using network analysis tools including Gene Ontology, and Ingenuity Pathway Analysis (Ingenuity Systems). Key findings were verified using real-time polymerase chain reaction and Western blots. RESULTS: Induction of hypothermia significantly (p < 0.05) decreased the magnitude of lactic acidosis and increased the survival rates (100% vs. 0% in normothermia group). Five hundred seventy-one of 23,000 genes had altered expression in response to the induction of hypothermia: 382 were up-regulated and 187 were down-regulated. Twelve key pathways were specifically modulated by hypothermia. Interleukin-6, interleukin-10, p38 mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells, glucocorticoids, and other signaling pathways involved with acute phase reactants were up-regulated. Multiple metabolic pathways were down- regulated. The largest change was in the peroxisome proliferator-activated receptor gamma gene that codes for a transcriptional coactivator, which in turn controls mitochondrial biogenesis, glycerolipid, and other metabolic pathways in the liver. Apoptotic cell death cascades were activated in response to blood loss (H and N groups), but multiple specific anti-apoptotic genes (baculoviral Inhibitor of apoptosis protein repeat-containing 3, BCL3L1, NFKB2) displayed an increased expression specifically in the hypothermia treated animals, suggesting an overall pro-survival phenotype. CONCLUSIONS: Profound hypothermia increases survival in a rodent model of hemorrhagic shock. In addition to decreasing tissue oxygen consumption, induction of hypothermia directly alters the expression profiles of key genes, with an overall up-regulation of pro-survival pathways and a down- regulation of metabolic pathways.

Acute pyelonephritis caused by Aerococcus urinae in a 12-year-old boy.

Aerococcus urinae are Gram-positive cocci that cause urinary tract infections in adults with underlying genitourinary (GU) tract disease. We report a case of pyelonephritis caused by A. urinae in a 12-year-old boy with a history of pyeloplasty and GU reflux.

NIH/Kennedy Center Workshop on Music and the Brain: Finding Harmony.

The National Institutes of Health and John F. Kennedy Center for the Performing Arts convened a panel of experts to discuss the current state of research on music and the brain. The panel generated research recommendations to accelerate the study of music's effects on the brain and the implications for human health.

Surviving lethal septic shock without fluid resuscitation in a rodent model.

BACKGROUND: We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, before a lethal dose of lipopolysaccharide (LPS) improves survival in mice. The purpose of the present study was to determine whether SAHA treatment would attenuate LPS-induced shock and improve survival when given postinsult in a rodent model. METHODS: C57BL/6J mice were intraperitoneally (IP) injected with LPS (30 mg/kg), and 2 hours later randomized into 2 groups: (1) vehicle animals (n = 10) received dimethyl sulfoxide (DMSO) solution only; and (2) SAHA animals (n = 10) were given SAHA (50 mg/kg, IP) in DMSO solution. Survival was monitored over the next 7 days. In a second study, LPS-injected mice were treated with either DMSO or SAHA as described, and normal (sham) animals served as controls. Lungs were harvested at 4, 6, and 8 hours after LPS injection for analysis of gene expression. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA post-treatment on LPS-induced inflammation using enzyme-linked immunosorbent assay. RESULTS: All LPS-injected mice that received the vehicle agent alone died within 24 hours, whereas the SAHA-treated animals displayed a significant improvement in 1 week survival (80% vs 0%; P < .001). LPS insult significantly enhanced gene expression of MyD88, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and was associated with an increased protein secretion of TNF-alpha and IL-6 into the cell culture medium. In contrast, SAHA treatment significantly attenuated all of these LPS-related alterations. CONCLUSION: We report for the first time that administration of SAHA (50 mg/kg IP) after a lethal dose of LPS significantly improves long-term survival, and attenuates expression of the proinflammatory mediators TNF-alpha and IL-6. Furthermore, our data suggest that the anti-inflammatory effects of SAHA may be due to downregulation of the MyD88-dependent pathway, and decreased expression of associated proinflammatory genes.

Protective effect of suberoylanilide hydroxamic acid against LPS-induced septic shock in rodents.

We have recently found that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lethal model of hemorrhagic shock in rats. The purpose of the present study was to determine whether SAHA treatment would prevent LPS-induced septic shock and improve the survival in a murine model. C57BL/6J mice were randomly divided into two groups. Experimental mice were given intraperitoneal SAHA (50 mg/kg) in vehicle dimethyl sulfoxide fluid (n = 10). The control mice (n = 10) received vehicle dimethyl sulfoxide only. They were injected with LPS (20 mg/kg, i.p.) 2 h later, and the animals from the treatment group were given a second dose of SAHA. Survival was monitored during the next 7 days. In a parallel study, mice treated with or without SAHA were subjected to LPS insult while normal (sham) mice serviced as controls. 1) Lungs were harvested at 3 and 48 h for analysis of gene expression and pathologic changes, respectively; 2) spleens were isolated for analysis of neutrophilic cell population. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA on LPS-induced inflammation in vitro. All mice in the control group that were subjected to LPS challenge died in less than 48 h. However, SAHA-treated animals displayed a significantly higher 1-week survival rate (87.5%) compared with the control group (0%). Moreover, LPS insult decreased the acetylation of histone proteins (H2A, H2B, and H3), elevated the levels of TNF-alpha in vivo (circulation) and in vitro (culture medium), increased the neutrophilic cell population in the spleen, enhanced the expression of TNF-alpha and IL-1beta genes in lung tissue, and augmented the pulmonary neutrophil infiltration. In contrast, SAHA treatment markedly attenuated all of these LPS-induced alterations. We report for the first time that administration of SAHA (50 mg/kg) significantly attenuates a variety of inflammatory markers and improves long-term survival after a lethal LPS insult.