Dr. Haileselassie completed his medical degree at University of Missouri followed by residency at University of Washington. He attained clinical training and expertise in pediatric critical care medicine along with a master’s in health sciences from the Johns Hopkins University. After fellowship, Dr. Haileselassie attained postdoctoral T32 research training under Dr. Theodore Abraham at Johns Hopkins University, which focused on myocardial mechanics and redox biology. This was complimented by his Instructorship at Stanford University where he received further research training in mitochondrial biology under Dr. Mochly-Rosen in the Department of Chemical Systems Biology. Dr. Haileselassie was recruited to Stanford School of Medicine in the University Medical Line in 2020, and currently runs an NIH-funded translational research program aimed at understanding the role of alterations in mitochondrial dynamics in sepsis induced multiple organ dysfunction syndrome (MODS).

Clinical Focus

  • Pediatric Critical Care Medicine

Academic Appointments

Honors & Awards

  • Awardee,, NRSA T-32 Grant Postdoctoral Research Training in Critical Care Medicine (2015-2016)
  • Awardee, Golden Apple Teaching Award,, Pediatric Critical Care Division (2017)
  • Awardee,, SCCM Gold Snapshot Award (2018)
  • Awardee, Pediatric Trauma and Critical Care Scientist Developmental Program (2017-2022)
  • Star Research Achievement Award, SCCM (2019)

Boards, Advisory Committees, Professional Organizations

  • Member, Maternal and Child Health Research Institute (MCHRI) (2018 - Present)
  • Member, American Academy of Pediatrics (2010 - Present)
  • Member, Society of Critical Care Medicine (2013 - Present)
  • Faculty, SCCM Critical Care Ultrasound (2014 - Present)

Professional Education

  • Residency: University of Washington Pediatric Residency (2013) WA
  • Medical Education: University of Missouri Kansas City School of Medicine Registrar (2010) MO
  • Board Certification: American Board of Pediatrics, Pediatric Critical Care Medicine (2016)
  • Fellowship: Johns Hopkins University Pediatric Critical Care Fellowship (2016) MD
  • Board Certification: American Board of Pediatrics, Pediatrics (2013)

Current Research and Scholarly Interests

My laboratory is focused on understanding the cellular mechanisms which mediate end-organ failure in pediatric sepsis. Our current work focuses on determining the role of altered mitochondrial dynamics in sepsis-induced multi-organ dysfunction syndrome (MODS). Specifically, we focus on understanding the mechanisms that mediate derangements in mitochondrial fission and autophagy in sepsis.

Stanford Advisees

All Publications

  • Extracellular release of mitochondria induced by pre-hematopoietic stem cell transplant conditioning exacerbates GVHD. Blood advances Vijayan, V., Yan, H., Lohmeyer, J. K., Prentiss, K. A., Patil, R. V., Barbarito, G., Lopez, I., Elezaby, A., Peterson, K., Baker, J., Ostberg, N. P., Bertaina, A., Negrin, R. S., Mochly-Rosen, D., Weinberg, K. I., Haileselassie, B. 2024


    Despite therapeutic advancements, GVHD is a major complication of HSCT. In current models of GVHD, tissue injury induced by cytotoxic conditioning regimens, along with translocation of microbes expressing Pathogen Associated Molecular Patterns (PAMPs), result in activation of host antigen-presenting cells (APC) to stimulate alloreactive donor T lymphocytes. Recent studies have demonstrated that in many pathologic states, tissue injury results in the release of mitochondria from the cytoplasm to the extracellular space. We hypothesized that extracellular mitochondria, which are related to archaebacteria, could also trigger GVHD by stimulation of host APC. We found that clinically relevant doses of radiation or busulfan induced extracellular release of mitochondria by various cell types, including cultured intestinal epithelial cells. Conditioning-mediated mitochondrial release was associated with mitochondrial damage and impaired quality control but did not affect the viability of the cells. Extracellular mitochondria directly stimulated host APCs to express higher levels of MHC-II, co-stimulatory CD86, and pro-inflammatory cytokines, resulting in increased donor T cell activation, and proliferation in mixed lymphocyte reactions. Analyses of plasma from both experimental mice and a cohort of children undergoing HSCT demonstrated that conditioning induced extracellular mitochondrial release in vivo. In mice undergoing MHC mismatched HSCT, administration of purified syngeneic extracellular mitochondria increased host APC activation and exacerbated GVHD. Our data suggests that pre-HSCT conditioning results in extracellular release of damaged mitochondria which increase alloreactivity and exacerbate GVHD. Therefore, decreasing the extracellular release of damaged mitochondria following conditioning could serve as a novel strategy for GVHD prevention.

    View details for DOI 10.1182/bloodadvances.2023012328

    View details for PubMedID 38701354

  • Biomarker Assessment of a High-Risk, Data-Driven Pediatric Sepsis Phenotype Characterized by Persistent Hypoxemia, Encephalopathy, and Shock. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Atreya, M. R., Bennett, T. D., Geva, A., Faustino, E. V., Rogerson, C. M., Lutfi, R., Cvijanovich, N. Z., Bigham, M. T., Nowak, J., Schwarz, A. J., Baines, T., Haileselassie, B., Thomas, N. J., Luo, Y., Sanchez-Pinto, L. N., Novel Data-Driven Sepsis Phenotypes in Children Study and the Genomics of Pediatric Septic Shock Investigators 2024


    OBJECTIVES: Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. We sought to the determine reproducibility of the data-driven "persistent hypoxemia, encephalopathy, and shock" (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk strata.DESIGN: We retrained and validated a random forest classifier using organ dysfunction subscores in the 2012-2018 electronic health record (EHR) dataset used to derive the PHES phenotype. We used this classifier to assign phenotype membership in a test set consisting of prospectively (2003-2023) enrolled pediatric septic shock patients. We compared profiles of the PERSEVERE family of biomarkers among those with and without the PHES phenotype and determined the association with established biomarker-based mortality and MODS risk strata.SETTING: Twenty-five PICUs across the United States.PATIENTS: EHR data from 15,246 critically ill patients with sepsis-associated MODS split into derivation and validation sets and 1,270 pediatric septic shock patients in the test set of whom 615 had complete biomarker data.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: The area under the receiver operator characteristic curve of the modified classifier to predict PHES phenotype membership was 0.91 (95% CI, 0.90-0.92) in the EHR validation set. In the test set, PHES phenotype membership was associated with both increased adjusted odds of complicated course (adjusted odds ratio [aOR] 4.1; 95% CI, 3.2-5.4) and 28-day mortality (aOR of 4.8; 95% CI, 3.11-7.25) after controlling for age, severity of illness, and immunocompromised status. Patients belonging to the PHES phenotype were characterized by greater degree of systemic inflammation and endothelial activation, and were more likely to be stratified as high risk based on PERSEVERE biomarkers predictive of death and persistent MODS.CONCLUSIONS: The PHES trajectory-based phenotype is reproducible, independently associated with poor clinical outcomes, and overlapped with higher risk strata based on prospectively validated biomarker approaches.

    View details for DOI 10.1097/PCC.0000000000003499

    View details for PubMedID 38465952

  • High Variability in the Duration of Chest Compression Interruption is Associated With Poor Outcomes in Pediatric Extracorporeal Cardiopulmonary Resuscitation. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Han, P., Rasmussen, L., Su, F., Dacre, M., Knight, L., Berg, M., Tawfik, D., Haileselassie, B. 2024


    To determine the association between chest compression interruption (CCI) patterns and outcomes in pediatric patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR).Cardiopulmonary resuscitation (CPR) data were collected using defibrillator-electrode and bedside monitor waveforms from pediatric ECPR cases between 2013 and 2021. Duration and variability of CCI during cannulation for ECPR was determined and compared with survival to discharge using Fishers exact test and logistic regressions with cluster-robust ses for adjusted analyses.Quaternary care children's hospital.Pediatric patients undergoing ECPR.None.Of 41 ECPR events, median age was 0.7 years (Q1, Q3: 0.1, 5.4), 37% (15/41) survived to hospital discharge with 73% (11/15) of survivors having a favorable neurologic outcome. Median duration of CPR from start of ECPR cannulation procedure to initiation of extracorporeal membrane oxygenation (ECMO) flow was 21 minutes (18, 30). Median duration of no-flow times associated with CCI during ECMO cannulation was 11 seconds (5, 28). Following planned adjustment for known confounders, survival to discharge was inversely associated with maximum duration of CCI (odds ratio [OR] 0.91 [0.86-0.95], p = 0.04) as well as the variability in the CCI duration (OR 0.96 [0.93-0.99], p = 0.04). Cases with both above-average CCI duration and higher CCI variability (sd> 30 s) were associated with lowest survival (12% vs. 54%, p = 0.009). Interaction modeling suggests that lower variability in CCI is associated with improved survival, especially in cases where average CCI durations are higher.Shorter duration of CCI and lower variability in CCI during cannulation for ECPR were associated with survival following refractory pediatric cardiac arrest.

    View details for DOI 10.1097/PCC.0000000000003461

    View details for PubMedID 38299932

  • Revisiting Post-ICU Admission Fluid Balance Across Pediatric Sepsis Mortality Risk Strata: A Secondary Analysis of a Prospective Observational Cohort Study. Critical care explorations Atreya, M. R., Cvijanovich, N. Z., Fitzgerald, J. C., Weiss, S. L., Bigham, M. T., Jain, P. N., Abulebda, K., Lutfi, R., Nowak, J., Thomas, N. J., Baines, T., Quasney, M., Haileselassie, B., Sahay, R., Zhang, B., Alder, M. N., Stanski, N. L., Goldstein, S. L. 2024; 6 (1): e1027


    OBJECTIVES: Post-ICU admission cumulative positive fluid balance (PFB) is associated with increased mortality among critically ill patients. We sought to test whether this risk varied across biomarker-based risk strata upon adjusting for illness severity, presence of severe acute kidney injury (acute kidney injury), and use of continuous renal replacement therapy (CRRT) in pediatric septic shock.DESIGN: Ongoing multicenter prospective observational cohort.SETTING: Thirteen PICUs in the United States (2003-2023).PATIENTS: Six hundred and eighty-one children with septic shock.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: Cumulative percent PFB between days 1 and 7 (days 1-7 %PFB) was determined. Primary outcome of interest was complicated course defined as death or persistence of greater than or equal to two organ dysfunctions by day 7. Pediatric Sepsis Biomarker Risk Model (PERSEVERE)-II biomarkers were used to assign mortality probability and categorize patients into high mortality (n = 91), intermediate mortality (n = 134), and low mortality (n = 456) risk strata. Cox proportional hazard regression models with adjustment for PERSEVERE-II mortality probability, presence of sepsis-associated acute kidney injury on day 3, and use of CRRT, demonstrated that time-dependent variable days 1-7%PFB was independently associated with an increased hazard of complicated course. Risk-stratified analyses revealed that each 10% increase in days 1-7 %PFB was associated with increased hazard of complicated course only among patients with high mortality risk strata (adjusted hazard ratio 1.24 (95% CI, 1.08-1.43), p = 0.003). However, this association was not causally mediated by PERSEVERE-II biomarkers.CONCLUSIONS: Our data demonstrate the influence of cumulative %PFB on the risk of complicated course in pediatric septic shock. Contrary to our previous report, this risk was largely driven by patients categorized as having a high mortality risk based on PERSEVERE-II biomarkers. Incorporation of such prognostic enrichment tools in randomized trials of restrictive fluid management or early initiation of de-escalation strategies may inform targeted application of such interventions among at-risk patients.

    View details for DOI 10.1097/CCE.0000000000001027

    View details for PubMedID 38234587

  • EPIDEMIOLOGY OF INTRACRANIAL HEMORRHAGE IN CHILDREN SUPPORTED BY EXTRACORPOREAL MEMBRANE OXYGENATION Mahmood, H., Alexander, P., Vogel, A., Thomas, C., Bembea, M., Norton, B., Schmoker, J., Rasmussen, L., Haileselassie, B., Todd-Tzanetos, D., Furlong-Dillard, J., Boville, B., Leimanis-Laurens, M., Viamonte, H., Amidon, M., Loftis, L., Nellis, M. LIPPINCOTT WILLIAMS & WILKINS. 2024
  • Derivation, validation, and transcriptomic assessment of pediatric septic shock phenotypes identified through latent profile analyses: Results from a prospective multi-center observational cohort. Research square Atreya, M. R., Huang, M., Moore, A. R., Zheng, H., Hasin-Brumshtein, Y., Fitzgerald, J. C., Weiss, S. L., Cvijanovich, N. Z., Bigham, M. T., Jain, P. N., Schwarz, A. J., Lutfi, R., Nowak, J., Thomas, N. J., Quasney, M., Dahmer, M. K., Baines, T., Haileselassie, B., Lautz, A. J., Stanski, N. L., Standage, S. W., Kaplan, J. M., Zingarelli, B., Sweeney, T. E., Khatri, P., Sanchez-Pinto, L. N., Kamaleswaran, R. 2023


    Sepsis poses a grave threat, especially among children, but treatments are limited due to clinical and biological heterogeneity among patients. Thus, there is an urgent need for precise subclassification of patients to guide therapeutic interventions.We used clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock cohort to derive phenotypes using latent profile analyses. Thereafter, we trained a support vector machine model to assign phenotypes in a hold-out validation set. We tested interactions between phenotypes and common sepsis therapies on clinical outcomes and conducted transcriptomic analyses to better understand the phenotype-specific biology. Finally, we compared whether newly identified phenotypes overlapped with established gene-expression endotypes and tested the utility of an integrated subclassification scheme.Among 1,071 patients included, we identified two phenotypes which we named 'inflamed' (19.5%) and an 'uninflamed' phenotype (80.5%). The 'inflamed' phenotype had an over 4-fold risk of 28-day mortality relative to those 'uninflamed'. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and suggested an overabundance of developing neutrophils, pro-T/NK cells, and NK cells among those 'inflamed'. There was no significant overlap between endotypes and phenotypes. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing endophenotypes.Our research underscores the reproducibility of latent profile analyses to identify clinical and biologically informative pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.

    View details for DOI 10.21203/

    View details for PubMedID 38105983

    View details for PubMedCentralID PMC10723552

  • Altered profiles of extracellular mitochondrial DNA in immunoparalyzed pediatric patients after thermal injury. Shock (Augusta, Ga.) Tetri, L. H., Penatzer, J. A., Tsegay, K. B., Tawfik, D. S., Burk, S., Lopez, I., Thakkar, R. K., Haileselassie, B. 2023


    Thermal injury is a major cause of morbidity and mortality in the pediatric population world-wide with secondary infection being the most common acute complication. Suppression of innate and adaptive immune function is predictive of infection in pediatric burn patients, but little is known about the mechanisms causing these effects. Circulating mtDNA which induces a proinflammatory signal, has been described in multiple disease states, but has not been studied in pediatric burn injuries. This study examined the quantity of circulating mtDNA and mtDNA mutations in immunocompetent (IC) and immunoparalyzed (IP) pediatric burn patients.Circulating DNA was isolated from plasma of pediatric burn patients treated at Nationwide Children's Hospital Burn Center at early (1-3 days) and late (4-7 days) time points post-injury. These patients were categorized as IP or IC based on previously established immune function testing and secondary infection. Three mitochondrial genes, D loop, ND1, and ND4, were quantified by multiplexed qPCR to assess both mtDNA quantity and mutation load.At the early timepoint, there were no differences in plasma mtDNA quantity, however IC patients had a progressive increase in mtDNA over time when compared to IP patients (change in ND1 copy number over time 3880 vs 87 copies/day, p = 0.0004). Conversely, the IP group had an increase in mtDNA mutation burden over time.IC patients experienced a significant increase in circulating mtDNA quantity over time, demonstrating an association between increased mtDNA release, and proinflammatory phenotype in the burn patients. IP patients had significant increases in mtDNA mutation load likely representative of degree of oxidative damage. Together, these data provide further insight into the inflammatory and immunological mechanisms following pediatric thermal injury.

    View details for DOI 10.1097/SHK.0000000000002253

    View details for PubMedID 38010095

  • Extracellular Release of Damaged Mitochondria Induced By Cytotoxic Conditioning Exacerbates Graft-Versus-Host Disease Vijayan, V., Yan, H., Lohmeyer, J., Prentiss, K., Patil, R., Barbarito, G., Lopez, I., Elezaby, A., Peterson, K., Baker, J., Ostberg, N., Bertaina, A., Negrin, R. S., Mochly-Rosen, D., Weinberg, K. I., Haileselassie, B. AMER SOC HEMATOLOGY. 2023
  • Serum Humanin in Pediatric Septic Shock Associated Multiple Organ Dysfunction Syndrome. Shock (Augusta, Ga.) Atreya, M. R., Piraino, G., Cvijanovich, N. Z., Fitzgerald, J. C., Weiss, S. L., Bigham, M. T., Jain, P. N., Schwarz, A. J., Lutfi, R., Nowak, J., Thomas, N. J., Baines, T., Haileselassie, B., Zingarelli, B. 2023


    BACKGROUND: Multiple organ dysfunction syndrome (MODS) disproportionately contributes to pediatric sepsis morbidity. Humanin (HN) is a small peptide encoded by mitochondrial DNA and thought to exert cytoprotective effects in endothelial cells and platelets. We sought to test the association between serum HN (sHN) concentrations and MODS in a prospectively enrolled cohort of pediatric septic shock.METHODS: Human MT-RNR2 ELISA was used to determine sHN concentrations on day 1 and 3. The primary outcome was thrombocytopenia associated multi-organ failure (TAMOF). Secondary outcomes included individual organ dysfunctions on day 7. Associations across pediatric sepsis biomarker (PERSEVERE) based mortality risk strata and correlation with platelet and markers endothelial activation were tested.RESULTS: 140 subjects were included in this cohort, of whom 39 had TAMOF. The concentration of sHN was higher on day 1 relative to day 3, and among those with TAMOF phenotype in comparison to those without. However, the association between sHN and TAMOF phenotype was not significant after adjusting for age and illness severity in multivariate models. In secondary analyses, sHN was associated with presence of day 7 sepsis-associated acute kidney injury (SA-AKI) (p = 0.049). Further, sHN was higher among those with high PERSEVERE-mortality risk strata and correlated with platelet counts and several markers of endothelial activation.CONCLUSION: Future investigation is necessary to validate the association between sHN and SA-AKI among children with septic shock. Further, mechanistic studies that elucidate the role of humanin may lead to therapies that promote organ recovery through restoration of mitochondrial homeostasis among those critically ill.

    View details for DOI 10.1097/SHK.0000000000002266

    View details for PubMedID 37917869

  • Serum Soluble Endoglin in Pediatric Septic Shock Associated Multiple Organ Dysfunction Syndrome. Shock (Augusta, Ga.) Atreya, M. R., Cvijanovich, N. Z., Fitzgerald, J. C., Weiss, S. L., Bigham, M. T., Jain, P. N., Schwarz, A. J., Lutfi, R., Nowak, J., Thomas, N. J., Quasney, M., Haileselassie, B., Baines, T. D., Zingarelli, B., Genomics of Pediatric Septic Shock Investigators 2023


    BACKGROUND: Endothelial activation is a key driver of multiple organ dysfunction syndrome (MODS). Soluble endoglin (sENG) is expressed by mature and progenitor endothelial cells and thought to have angiogenic properties. We sought to determine the association between sENG and pediatric sepsis associated MODS.METHODS: Prospective observational study of pediatric septic shock. Primary outcome of interest was complicated course -a composite of death by (or) MODS on day 7 of illness. Secondary outcomes included individual organ dysfunctions. Endothelial biomarkers including sENG were measured using multiplex Luminex assays among patients with existing data on pediatric sepsis biomarker risk model data (PERSEVERE-II). Multivariable regression was used to test the independent association between sENG and clinical outcomes. Serum sENG concentrations across PERSEVERE-II mortality risk strata and correlations with established markers of endothelial dysfunction.RESULTS: 306 critically ill children with septic shock were included. Serum sENG concentrations were higher among those with primary and secondary outcomes of interest, with the exception of acute neurological dysfunction. sENG was independently associated with increased odds of complicated course [adj OR 1.53 (95% CI: 1.02-2.27), p = 0.038] and acute renal dysfunction [adj OR 1.84 (95%CI: 1.18-2.876), p = 0.006]. sENG demonstrated graded responses across PERSEVERE-II risk strata and was positively correlated with endothelial biomarkers, except Angiopoietin-1.CONCLUSIONS: Serum soluble endoglin is independently associated with complicated course and acute renal dysfunction in pediatric septic shock. Future studies are required to validate our observational data and mechanistic studies are necessary to elucidate whether endoglin plays a organ-specific role in development or resolution of acute renal dysfunction in sepsis.

    View details for DOI 10.1097/SHK.0000000000002183

    View details for PubMedID 37493567

  • Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction. Nature communications Rios, L., Pokhrel, S., Li, S. J., Heo, G., Haileselassie, B., Mochly-Rosen, D. 2023; 14 (1): 4356


    The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to mitochondrial Fis1 and subsequently, mitochondrial fragmentation, ROS production, metabolic collapse, and cell death. Because Drp1 also mediates physiological fission by binding to mitochondrial Mff, therapeutics that inhibit pathological fission should spare physiological mitochondrial fission. P110, a peptide inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models of neurodegeneration, ischemia, and sepsis without blocking the physiological functions of Drp1. Since peptides have pharmacokinetic limitations, we set out to identify small molecules that mimic P110's benefit. We map the P110-binding site to a switch I-adjacent grove (SWAG) on Drp1. Screening for SWAG-binding small molecules identifies SC9, which mimics P110's benefits in cells and a mouse model of endotoxemia. We suggest that the SWAG-binding small molecules discovered in this study may reduce the burden of Drp1-mediated pathologies and potentially pathologies associated with other members of the GTPase family.

    View details for DOI 10.1038/s41467-023-40043-0

    View details for PubMedID 37468472

    View details for PubMedCentralID PMC10356917

  • Prognostic and predictive value of endothelial dysfunction biomarkers in sepsis-associated acute kidney injury: risk-stratified analysis from a prospective observational cohort of pediatric septic shock. Critical care (London, England) Atreya, M. R., Cvijanovich, N. Z., Fitzgerald, J. C., Weiss, S. L., Bigham, M. T., Jain, P. N., Schwarz, A. J., Lutfi, R., Nowak, J., Allen, G. L., Thomas, N. J., Grunwell, J. R., Baines, T., Quasney, M., Haileselassie, B., Alder, M. N., Goldstein, S. L., Stanski, N. L. 2023; 27 (1): 260


    BACKGROUND: Sepsis-associated acute kidney injury (SA-AKI) is associated with high morbidity, with no current therapies available beyond continuous renal replacement therapy (CRRT). Systemic inflammation and endothelial dysfunction are key drivers of SA-AKI. We sought to measure differences between endothelial dysfunction markers among children with and without SA-AKI, test whether this association varied across inflammatory biomarker-based risk strata, and develop prediction models to identify those at highest risk of SA-AKI.METHODS: Secondary analyses of prospective observational cohort of pediatric septic shock. Primary outcome of interest was the presence of≥Stage II KDIGO SA-AKI on day 3 based on serum creatinine (D3 SA-AKI SCr). Biomarkers including those prospectively validated to predict pediatric sepsis mortality (PERSEVERE-II) were measured in Day 1 (D1) serum. Multivariable regression was used to test the independent association between endothelial markers and D3 SA-AKI SCr. We conducted risk-stratified analyses and developed prediction models using Classification and Regression Tree (CART), to estimate risk of D3 SA-AKI amongprespecified subgroups based on PERSEVERE-II risk.RESULTS: A total of 414 patients were included in the derivation cohort. Patients with D3 SA-AKI SCr had worse clinical outcomes including 28-day mortality and need for CRRT. Serum soluble thrombomodulin (sTM), Angiopoietin-2 (Angpt-2), and Tie-2 were independently associated with D3 SA-AKI SCr. Further, Tie-2 and Angpt-2/Tie-2 ratios were influenced by the interaction between D3 SA-AKI SCr and risk strata. Logistic regression demonstrated models predictive of D3 SA-AKI risk performed optimally among patients with high- or intermediate-PERSEVERE-II risk strata. A 6 terminal node CART model restricted to this subgroup of patients had an area under the receiver operating characteristic curve (AUROC) 0.90 and 0.77 upon tenfold cross-validation in the derivation cohort to distinguish those with and without D3 SA-AKI SCr and high specificity. The newly derived model performed modestly in a unique set of patients (n=224), 84 of whom were deemed high- or intermediate-PERSEVERE-II risk, to distinguish those patients with high versus low risk of D3 SA-AKI SCr.CONCLUSIONS: Endothelial dysfunction biomarkers are independently associated with risk of severe SA-AKI. Pending validation, incorporation of endothelial biomarkers may facilitate prognostic and predictive enrichment for selection of therapeutics in future clinical trials among critically ill children.

    View details for DOI 10.1186/s13054-023-04554-y

    View details for PubMedID 37400882

  • Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1. Critical care (London, England) Atreya, M. R., Cvijanovich, N. Z., Fitzgerald, J. C., Weiss, S. L., Bigham, M. T., Jain, P. N., Schwarz, A. J., Lutfi, R., Nowak, J., Allen, G. L., Thomas, N. J., Grunwell, J. R., Baines, T., Quasney, M., Haileselassie, B., Alder, M. N., Lahni, P., Ripberger, S., Ekunwe, A., Campbell, K. R., Walley, K. R., Standage, S. W. 2023; 27 (1): 250


    BACKGROUND: Sepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR)mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults. In contrast, we have previously demonstrated higher mortality in the juvenile host. Given the potential pleiotropic effects of PCSK9 on the endothelium, beyond canonicaleffects on serum lipoproteins, both of which may influence sepsis outcomes, we sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction.METHODS: Secondary analyses of a prospective observational cohort of pediatric septic shock. Genetic variants of PCSK9 and LDLR genes, serum PCSK9, and lipoprotein concentrations were determined previously. Endothelial dysfunction markers were measured in day 1 serum. We conducted multivariable linear regression to test the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses to test impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified.RESULTS: A total of 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of those homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 was not correlated with endothelial dysfunction. PCSK9 LOF influenced concentrations of Angiopoietin-1 (Angpt-1) upon adjusting for potential confounders including lipoprotein concentrations, with false discovery adjusted p value of 0.042 and 0.013 for models that included LDL and HDL, respectively. Causal mediation analysis demonstrated that the effect of PCSK9 LOF on mortality was mediated by Angpt-1 (p=0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype.CONCLUSIONS: We present genetic and biomarker association data that suggest a potential direct role of the PCSK9-LDLR pathway on Angpt-1 in the developing host with septic shock and warrant external validation. Further, mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of pediatric-specific sepsis therapies.

    View details for DOI 10.1186/s13054-023-04535-1

    View details for PubMedID 37365661

  • Serum renin and prorenin concentrations predict severe persistent acute kidney injury and mortality in pediatric septic shock. Pediatric nephrology (Berlin, Germany) Stanski, N. L., Shakked, N. P., Zhang, B., Cvijanovich, N. Z., Fitzgerald, J. C., Jain, P. N., Schwarz, A. J., Nowak, J., Weiss, S. L., Allen, G. L., Thomas, N. J., Haileselassie, B., Goldstein, S. L. 2023


    BACKGROUND: Studies in critically ill adults demonstrate associations between serum renin concentrations (a proposed surrogate for renin-angiotensin-aldosterone system dysregulation) and poor outcomes, but data in critically ill children are lacking. We assessed serum renin+prorenin concentrations in children with septic shock to determine their predictive ability for acute kidney injury (AKI) and mortality.METHODS: We conducted a secondary analysis of a multicenter observational study of children aged 1week to 18years admitted to 14 pediatric intensive care units (PICUs) with septic shock and residual serum available for renin+prorenin measurement. Primary outcomes were development of severe persistent AKI (≥KDIGO stage 2 for≥48h) in the first week and 28-day mortality.RESULTS: Among 233 patients, day 1 median renin+prorenin concentration was 3436pg/ml (IQR 1452-6567). Forty-two (18%) developed severe persistent AKI and 32 (14%) died. Day 1 serum renin+prorenin predicted severe persistent AKI with an AUROC of 0.75 (95% CI 0.66-0.84, p<0.0001; optimal cutoff 6769pg/ml) and mortality with an AUROC of 0.79 (95% CI 0.69-0.89, p<0.0001; optimal cutoff 6521pg/ml). Day 3/day 1 (D3:D1) renin+prorenin ratio had an AUROC of 0.73 (95% CI 0.63-0.84, p<0.001) for mortality. On multivariable regression, day 1 renin+prorenin>optimal cutoff retained associations with severe persistent AKI (aOR 6.8, 95% CI 3.0-15.8, p<0.001) and mortality (aOR 6.9, 95% CI 2.2-20.9, p<0.001). Similarly, D3:D1 renin+prorenin>optimal cutoff was associated with mortality (aOR 7.6, 95% CI 2.5-23.4, p<0.001).CONCLUSIONS: Children with septic shock have very elevated serum renin+prorenin concentrations on PICU admission, and these concentrations, as well as their trend over the first 72h, predict severe persistent AKI and mortality. A higher resolution version of the Graphical abstract is available as Supplementary information.

    View details for DOI 10.1007/s00467-023-05930-0

    View details for PubMedID 36939916

  • Prevalence and prognostic implications of hypertensive response to exercise in patients with hypertrophic cardiomyopathy. International journal of cardiology. Cardiovascular risk and prevention Lu, D. Y., Ventoulis, I., Liu, H., Haileselassie, B., Pozios, I., Liang, H. Y., Sorensen, L. L., Canepa, M., Bavaro, N., Phillip, S., Abraham, M. R., Abraham, T. P. 2023; 16: 200166


    Hypertensive response to exercise (HRE) is observed in patients with hypertrophic cardiomyopathy (HCM) with normal resting blood pressure (BP). However, the prevalence or prognostic implications of HRE in HCM remain unclear.In this study, normotensive HCM subjects were enrolled. HRE was defined as systolic BP > 210 mmHg in men or >190 mmHg in women, or diastolic BP > 90 mmHg, or an increase in diastolic BP > 10 mmHg during treadmill exercise. All participants were followed for subsequent development of hypertension, atrial fibrillation (AF), heart failure (HF), sustained ventricular tachycardia/fibrillation (VT/VF), and all-cause death. Six hundred and eighty HCM patients were screened.347 patients had baseline hypertension, and 333 patients were baseline normotensive. 132 (40%) of the 333 patients had HRE. HRE was associated with female sex, lower body mass index and milder left ventricular outflow tract obstruction. Exercise duration and metabolic equivalents were similar between patients with or without HRE, but the HRE group had higher peak heart rate (HR), better chronotropic response and more rapid HR recovery. Conversely, non-HRE patients were more likely to exhibit chronotropic incompetence and hypotensive response to exercise. After a mean follow-up of 3.4 years, patients with and without HRE had similar risks of progression to hypertension, AF, HF, sustained VT/VF or death.HRE is common in normotensive HCM patients during exercise. HRE did not carry higher risks of future hypertension or cardiovascular adverse outcomes. Conversely, the absence of HRE was associated with chronotropic incompetence and hypotensive response to exercise.

    View details for DOI 10.1016/j.ijcrp.2022.200166

    View details for PubMedID 36874040

    View details for PubMedCentralID PMC9975236

  • Drp1/p53 interaction mediates p53 mitochondrial localization and dysfunction in septic cardiomyopathy. Journal of molecular and cellular cardiology Mukherjee, R., Tetri, L. H., Li, S. J., Fajardo, G., Ostberg, N. P., Tsegay, K. B., Gera, K., Cornell, T. T., Bernstein, D., Mochly-Rosen, D., Haileselassie, B. 2023; 177: 28-37


    Previous studies have implicated p53-dependent mitochondrial dysfunction in sepsis induced end organ injury, including sepsis-induced myocardial dysfunction (SIMD). However, the mechanisms behind p53 localization to the mitochondria have not been well established. Dynamin-related protein 1 (Drp1), a mediator of mitochondrial fission, may play a role in p53 mitochondrial localization. Here we examined the role of Drp1/p53 interaction in SIMD using in vitro and murine models of sepsis.H9c2 cardiomyoblasts and BALB/c mice were exposed to lipopolysaccharide (LPS) to model sepsis phenotype. Pharmacologic inhibitors of Drp1 activation (ψDrp1) and of p53 mitochondrial binding (pifithrin μ, PFTμ) were utilized to assess interaction between Drp1 and p53, and the subsequent downstream impact on mitochondrial morphology and function, cardiomyocyte function, and sepsis phenotype.Both in vitro and murine models demonstrated an increase in physical Drp1/p53 interaction following LPS treatment, which was associated with increased p53 mitochondrial localization, and mitochondrial dysfunction. This Drp1/p53 interaction was inhibited by ΨDrp1, suggesting that this interaction is dependent on Drp1 activation. Treatment of H9c2 cells with either ΨDrp1 or PFTμ inhibited the LPS mediated localization of Drp1/p53 to the mitochondria, decreased oxidative stress, improved cellular respiration and ATP production. Similarly, treatment of BALB/c mice with either ΨDrp1 or PFTμ decreased LPS-mediated mitochondrial localization of p53, mitochondrial ROS in cardiac tissue, and subsequently improved cardiomyocyte contractile function and survival.Drp1/p53 interaction and mitochondrial localization is a key prodrome to mitochondrial damage in SIMD and inhibiting this interaction may serve as a therapeutic target.

    View details for DOI 10.1016/j.yjmcc.2023.01.008

    View details for PubMedID 36841153

  • MODIFIED ASSESSMENT OF COMPETENCY IN THORACIC SONOGRAPHY (ACTS) SCALE IN THE NICU AND PICU Dasani, R., Bhargava, V., Chan, B., Hamilton, C., Seekins, J., Halabi, S., Chen, D., Reddy, C., Hilgenberg, S., Haileselassie, B., Bhombal, S. LIPPINCOTT WILLIAMS & WILKINS. 2023: 302
  • Prediction of Difficult Laryngoscopy Using Ultrasound: A Systematic Review and Meta-Analysis. Critical care medicine Bhargava, V., Rockwell, N. A., Tawfik, D., Haileselassie, B., Petrisor, C., Su, E. 2023; 51 (1): 117-126


    OBJECTIVES: Evaluate associations between ultrasound measures and difficult laryngoscopy.DATA SOURCES: MEDLINE, Embase, Google Scholar, Web of Science, and the Cochrane Library were searched using MeSH terms and keywords.STUDY SELECTION: Studies published in English describing the use of airway ultrasound for identifying difficult laryngoscopy, with sufficient data to calculate sensitivity and specificity using 2*2 tables.DATA EXTRACTION: We assigned the described indices of airway dimension to one of three domains based on methodology characteristics: anterior tissue thickness domain, anatomical position domain, and oral space domain. We then performed a bivariate random-effects meta-analysis, deriving pooled sensitivity, specificity, diagnostic odds ratio, positive likelihood ratio, and negative likelihood ratio estimates. We assessed risks of bias using Quality Assessment of Diagnostic Accuracy Studies-2 analysis.DATA SYNTHESIS: Thirty-three studies evaluating 27 unique indices were included in the meta-analysis. The ultrasound protocols of the included studies were heterogeneous. Anterior tissue thickness demonstrated a pooled sensitivity of 76% (95% CI, 71-81%), specificity of 77% (95% CI, 72-81%), and an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.80-0.86). Anatomical position demonstrated a pooled sensitivity of 74% (95% CI, 61-84%), specificity of 86% (95% CI, 78-91%), and an AUROC of 0.87 (95% CI, 0.84-0.90). Oral space demonstrated a pooled sensitivity of 53% (95% CI, 0.36-0.69), specificity of 77% (95% CI, 0.67-0.85), and an AUROC of 0.73 (95% CI, 0.69-0.77).CONCLUSIONS: Airway ultrasound metrics associate with difficult laryngoscopy in three domains: anterior tissue thickness, anatomic position, and oral space. An assessment instrument combining clinical and ultrasound assessments may be an accurate screening tool for difficult laryngoscopy.

    View details for DOI 10.1097/CCM.0000000000005711

    View details for PubMedID 36519985

  • External validation of the modified sepsis renal angina index for prediction of severe acute kidney injury in children with septic shock. Critical care (London, England) Stanski, N. L., Basu, R. K., Cvijanovich, N. Z., Fitzgerald, J. C., Bigham, M. T., Jain, P. N., Schwarz, A. J., Lutfi, R., Thomas, N. J., Baines, T., Haileselassie, B., Weiss, S. L., Atreya, M. R., Lautz, A. J., Zingarelli, B., Standage, S. W., Kaplan, J., Chawla, L. S., Goldstein, S. L. 2023; 27 (1): 463


    BACKGROUND: Acute kidney injury (AKI) occurs commonly in pediatric septic shock and increases morbidity and mortality. Early identification of high-risk patients can facilitate targeted intervention to improve outcomes. We previously modified the renal angina index (RAI), a validated AKI prediction tool, to improve specificity in this population (sRAI). Here, we prospectively assess sRAI performance in a separate cohort.METHODS: A secondary analysis of a prospective, multicenter, observational study of children with septic shock admitted to the pediatric intensive care unit from 1/2019 to 12/2022. The primary outcome was severe AKI (≥KDIGO Stage 2) on Day 3 (D3 severe AKI), and we compared predictive performance of the sRAI (calculated on Day 1) to the original RAI and serum creatinine elevation above baseline (D1 SCr>Baseline+). Original renal angina fulfillment (RAI+) was defined as RAI≥8; sepsis renal angina fulfillment (sRAI+) was defined as RAI≥20 or RAI 8 to<20 with platelets<150*103/L.RESULTS: Among 363 patients, 79 (22%) developed D3 severe AKI. One hundred forty (39%) were sRAI+, 195 (54%) RAI+, and 253 (70%) D1 SCr>Baseline+. Compared to sRAI-, sRAI+had higher risk of D3 severe AKI (RR 8.9, 95%CI 5-16, p<0.001), kidney replacement therapy (KRT) (RR 18, 95%CI 6.6-49, p<0.001), and mortality (RR 2.5, 95%CI 1.2-5.5, p=0.013). sRAI predicted D3 severe AKI with an AUROC of 0.86 (95%CI 0.82-0.90), with greater specificity (74%) than D1 SCr>Baseline (36%) and RAI+(58%). On multivariable regression, sRAI+retained associations with D3 severe AKI (aOR 4.5, 95%CI 2.0-10.2, p<0.001) and need for KRT (aOR 5.6, 95%CI 1.5-21.5, p=0.01).CONCLUSIONS: Prediction of severe AKI in pediatric septic shock is important to improve outcomes, allocate resources, and inform enrollment in clinical trials examining potential disease-modifying therapies. The sRAI affords more accurate and specific prediction than context-free SCr elevation or the original RAI in this population.

    View details for DOI 10.1186/s13054-023-04746-6

    View details for PubMedID 38017578

  • A point-of-care ultrasound education curriculum for pediatric critical care medicine. The ultrasound journal Bhargava, V., Haileselassie, B., Rosenblatt, S., Baker, M., Kuo, K., Su, E. 2022; 14 (1): 44


    BACKGROUND: Diagnostic and procedural point-of-care ultrasound (POCUS) change patient management with the potential to improve outcomes. Pediatric critical care medicine trainees have limited access to education and training opportunities in diagnostic POCUS in the pediatric ICU. A dearth of published pediatric ICU curricular resources restricts these educational opportunities.METHODS: A 7-week longitudinal curriculum including lectures, practical skills sessions, and knowledge assessment covering core modules including (1) machine operation, (2) vascular access, (3) non-vascular procedures, (4) cardiac imaging, (5) hemodynamic assessment, (6) pulmonary imaging, and (7) abdominal imaging, was disseminated to pediatric critical care trainees and faculty at a single tertiary care pediatric hospital.RESULTS: The knowledge of trainees and participating faculty in procedural and diagnostic POCUS improved after implementing the curriculum. Pre-test scores mean and standard deviation (59.30%±14.15%) improved significantly (75.60%±9.43%) for all learners (p<0.001). The overall self-reported comfort in diagnostic and procedural ultrasound improved for all learners. 100% of the learners reported utilizing diagnostic POCUS in their clinical practice four months after disseminating the curriculum.DISCUSSION: We describe a single center's approach to POCUS education with improvement in knowledge, self-reported comfort, and attitudes towards procedural and diagnostic POCUS. The curricular resources for adaptation in a similar educational context are provided.

    View details for DOI 10.1186/s13089-022-00290-6

    View details for PubMedID 36315345

  • Integrated PERSEVERE and endothelial biomarker risk model predicts death and persistent MODS in pediatric septic shock: a secondary analysis of a prospectiveobservationalstudy. Critical care (London, England) Atreya, M. R., Cvijanovich, N. Z., Fitzgerald, J. C., Weiss, S. L., Bigham, M. T., Jain, P. N., Schwarz, A. J., Lutfi, R., Nowak, J., Allen, G. L., Thomas, N. J., Grunwell, J. R., Baines, T., Quasney, M., Haileselassie, B., Lindsell, C. J., Alder, M. N., Wong, H. R. 2022; 26 (1): 210


    BACKGROUND: Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock.METHODS: We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6-biomarker model was developed thereafter.RESULTS: Among 502 patients, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91-0.95) with a summary AUROC of 0.80 (0.76-0.84) upon tenfold cross-validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin, performed similarly. Interaction between variables-ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1-contributed to the models' predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging from 0.91 to 0.97 and 0.68 to 0.89 in training and test sets, respectively.CONCLUSIONS: The newly derived PERSEVEREnce biomarker model reliably estimates risk of death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics.

    View details for DOI 10.1186/s13054-022-04070-5

    View details for PubMedID 35818064

  • Implementation of a Bedside Point-of-Care Ultrasound Program in a Large Academic Neonatal Intensive Care Unit. American journal of perinatology Pai, V. V., Noh, C. Y., Dasani, R., Vallandingham, S., Manipon, C., Haileselassie, B., Profit, J., Balasundaram, M., Davis, A. S., Bhombal, S. 2022


     In the adult and pediatric critical care population, point-of-care ultrasound (POCUS) can aid in diagnosis, patient management, and procedural accuracy. For neonatal providers, training in ultrasound and the use of ultrasound for diagnosis and management is increasing, but use in the neonatal intensive care unit (NICU) is still uncommon compared with other critical care fields. Our objective was to describe the process of implementing a POCUS program in a large academic NICU and evaluate the role of ultrasound in neonatal care during early adaption of this program. A POCUS program established in December 2018 included regular bedside scanning, educational sessions, and quality assurance, in collaboration with members of the cardiology, radiology, and pediatric critical care divisions. Core applications were determined, and protocols outlined guidelines for image acquisition. An online database included images and descriptive logs for each ultrasound. A total of 508 bedside ultrasounds (76.8% diagnostic and 23.2% procedural) were performed by 23 providers from December 2018 to December 2020 in five core diagnostic applications: umbilical line visualization, cardiac, lung, abdomen (including bladder), and cranial as well as procedural applications. POCUS guided therapy and influenced clinical management in all applications: umbilical line assessment (26%), cardiac (33%), lung (14%), abdomen (53%), and cranial (43%). With regard to procedural ultrasound, 74% of ultrasound-guided arterial access and 89% of ultrasound-guided lumbar punctures were successful. Implementation of a POCUS program is feasible in a large academic NICU and can benefit from a team approach. Establishing a program in any NICU requires didactic opportunities, a defined scope of practice, and imaging review with quality assurance. Bedside clinician performed ultrasound findings can provide valuable information in the NICU and impact clinical management.· Use of point-of-care ultrasound is increasing in neonatology and has been shown to improve patient care.. · Implementation of a point-of-care ultrasound program requires the definition of scope of practice and can benefit from the support of other critical care and imaging departments and providers.. · Opportunities for point-of-care ultrasound didactics, imaging review, and quality assurance can enhance the utilization of bedside ultrasound..

    View details for DOI 10.1055/s-0042-1750118

    View details for PubMedID 35691294

  • Drp1/Fis1-Dependent Pathologic Fission and Associated Damaged Extracellular Mitochondria Contribute to Macrophage Dysfunction in Endotoxin Tolerance. Critical care medicine Mukherjee, R., Tompkins, C. A., Ostberg, N. P., Joshi, A. U., Massis, L. M., Vijayan, V., Gera, K., Monack, D., Cornell, T. T., Hall, M. W., Mochly-Rosen, D., Haileselassie, B. 1800


    OBJECTIVES: Recent publications have shown that mitochondrial dynamics can govern the quality and quantity of extracellular mitochondria subsequently impacting immune phenotypes. This study aims to determine if pathologic mitochondrial fission mediated by Drp1/Fis1 interaction impacts extracellular mitochondrial content and macrophage function in sepsis-induced immunoparalysis.DESIGN: Laboratory investigation.SETTING: University laboratory.SUBJECTS: C57BL/6 and BALB/C mice.INTERVENTIONS: Using in vitro and murine models of endotoxin tolerance (ET), we evaluated changes in Drp1/Fis1-dependent pathologic fission and simultaneously measured the quantity and quality of extracellular mitochondria. Next, by priming mouse macrophages with isolated healthy mitochondria (MC) and damaged mitochondria, we determined if damaged extracellular mitochondria are capable of inducing tolerance to subsequent endotoxin challenge. Finally, we determined if inhibition of Drp1/Fis1-mediated pathologic fission abrogates release of damaged extracellular mitochondria and improves macrophage response to subsequent endotoxin challenge.MEASUREMENTS AND MAIN RESULTS: When compared with naive macrophages (NMs), endotoxin-tolerant macrophages (ETM) demonstrated Drp1/Fis1-dependent mitochondrial dysfunction and higher levels of damaged extracellular mitochondria (Mitotracker-Green + events/50 muL: ETM = 2.42 * 106 ± 4,391 vs NM = 5.69 * 105 ± 2,478; p < 0.001). Exposure of NMs to damaged extracellular mitochondria (MH) induced cross-tolerance to subsequent endotoxin challenge, whereas MC had minimal effect (tumor necrosis factor [TNF]-alpha [pg/mL]: NM = 668 ± 3, NM + MH = 221 ± 15, and NM + Mc = 881 ± 15; p < 0.0001). Inhibiting Drp1/Fis1-dependent mitochondrial fission using heptapeptide (P110), a selective inhibitor of Drp1/Fis1 interaction, improved extracellular mitochondrial function (extracellular mitochondrial membrane potential, JC-1 [R/G] ETM = 7 ± 0.5 vs ETM + P110 = 19 ± 2.0; p < 0.001) and subsequently improved immune response in ETMs (TNF-alpha [pg/mL]; ETM = 149 ± 1 vs ETM + P110 = 1,150 ± 4; p < 0.0001). Similarly, P110-treated endotoxin tolerant mice had lower amounts of damaged extracellular mitochondria in plasma (represented by higher extracellular mitochondrial membrane potential, TMRM/MT-G: endotoxin tolerant [ET] = 0.04 ± 0.02 vs ET + P110 = 0.21 ± 0.02; p = 0.03) and improved immune response to subsequent endotoxin treatment as well as cecal ligation and puncture.CONCLUSIONS: Inhibition of Drp1/Fis1-dependent mitochondrial fragmentation improved macrophage function and immune response in both in vitro and in vivo models of ET. This benefit is mediated, at least in part, by decreasing the release of damaged extracellular mitochondria, which contributes to endotoxin cross-tolerance. Altogether, these data suggest that alterations in mitochondrial dynamics may play an important role in sepsis-induced immunoparalysis.

    View details for DOI 10.1097/CCM.0000000000005437

    View details for PubMedID 35067534

  • Laryngeal Ultrasound Detects Vocal Fold Immobility in Adults: A Systematic Review. Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine Su, E., Hamilton, C., Tawfik, D. S., Mariano, K., Ginsburg, S., Conlon, T., Veten, A., Fernandez, E., Wong, K., Sidell, D. R., Haileselassie, B., Pediatric Research Collaborative for Critical Ultrasound 2021


    Laryngeal ultrasound (US) is becoming widely accepted for assessing true vocal fold immobility (TVFI), a potential complication of laryngeal and thyroid surgery. The objective of this project is to perform a systematic review and meta-analysis of pooled evidence surrounding laryngeal US as a modality for diagnosing TVFI in adults at risk for the condition in comparison to laryngoscopy as a gold standard. Medical subject heading terms were used to search MEDLINE, Embase, Google Scholar, Web of Science, and the Cochrane Library for relevant citations from January 1, 2000, to June 30, 2020. Studies were included if they involved patients 16years and older, where laryngeal US was compared to laryngoscopy for TVFI. Studies were excluded if there were insufficient data to compute a sensitivity/specificity table after attempting to contact the authors. Case reports, and case series were also excluded. The initial search returned 1357 citations. Of these, 109 were selected for review utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Thirty citations describing 6033 patients were included in the final meta-analysis. A bivariate random effects meta-analysis was performed, revealing a pooled sensitivity for laryngeal US of 0.95 (95% confidence interval [CI] 0.88-0.98), a specificity of 0.99 (95% CI 0.97-0.99), and a diagnostic odds ratio of 1328.2 (95% CI 294.0-5996.5). The area under the curve of the hierarchical summary receiver operating characteristic curve was 0.99 (95% CI 0.98-1.00). Laryngeal US demonstrates high sensitivity and specificity for detecting VFI in the hands of clinicians directly providing care to patients.

    View details for DOI 10.1002/jum.15884

    View details for PubMedID 34837415

  • deltaPKC-Mediated Drp1 Phosphorylation Impacts Macrophage Mitochondrial Function and Inflammatory Response to Endotoxin. Shock (Augusta, Ga.) Lin, A. J., Joshi, A. U., Mukherjee, R., Tompkins, C. A., Vijayan, V., Mochly-Rosen, D., Haileselassie, B. 2021


    BACKGROUND: Recent studies have demonstrated that alterations in mitochondrial dynamics can impact innate immune function. However, the upstream mechanisms which link mitochondrial dynamics to innate immune phenotypes have not been completely elucidated. This study asks if deltaPKC-mediated phosphorylation of Drp1, a key driver of mitochondrial fission, impacts macrophage pro-inflammatory response following bacterial-derived lipopolysaccharide (LPS) stimulation.METHODS: Using RAW 264.7 cells, bone marrow-derived macrophages from C57BL/6J mice, as well as human monocyte-derived macrophages, we first characterized changes in deltaPKC-mediated phosphorylation of Drp1 following LPS stimulation. Next, using rationally-designed peptides that inhibit deltaPKC activation (deltaV1-1) and deltaPKC-Drp1 interaction (psiDrp1), we determined whether deltaPKC-mediated phosphorylation of Drp1 impacts LPS-induced changes in mitochondrial morphology, mitochondrial function, and inflammatory response.RESULTS: Our results demonstrated that deltaPKC-dependent Drp1 activation is associated with increased mitochondrial fission, impaired cellular respiration, and increased mitochondrial reactive oxygen species in LPS-treated macrophages. This is reversed using a rationally-designed peptide which selectively inhibits deltaPKC phosphorylation of Drp1 (psiDrp1). Interestingly, limiting excessive mitochondrial fission using psiDrp1 reduced LPS-triggered pro-inflammatory response, including a decrease in NF-kappaB nuclear localization, decreased iNOS induction, and a reduction in pro-inflammatory cytokines (IL-1beta, TNFalpha, IL-6).CONCLUSION: These data suggest that inhibiting Drp1 phosphorylation by deltaPKC abates the excessive mitochondrial fragmentation and mitochondrial dysfunction that is seen following LPS treatment. Furthermore, these data suggest that limiting deltaPKC-dependent Drp1 activation decreases the pro-inflammatory response following LPS treatment. Altogether, deltaPKC-dependent Drp1 phosphorylation might be an upstream mechanistic link between alterations in mitochondrial dynamics and innate immune phenotypes, and may have therapeutic potential.

    View details for DOI 10.1097/SHK.0000000000001885

    View details for PubMedID 34738957

  • Recalibration of the Renal Angina Index for Pediatric Septic Shock KIDNEY INTERNATIONAL REPORTS Stanski, N. L., Wong, H. R., Basu, R. K., Cvijanovich, N. Z., Fitzgerald, J. C., Weiss, S. L., Bigham, M. T., Jain, P. N., Schwarz, A., Lutfi, R., Nowak, J., Allen, G. L., Thomas, N. J., Grunwell, J. R., Quasney, M., Haileselassie, B., Chawla, L. S., Goldstein, S. L. 2021; 6 (7): 1858-1867
  • Estimating filling pressures in paediatric heart transplant recipients using echocardiographic parameters and B-type natriuretic peptide. Cardiology in the young Wisotzkey, B. L., Haileselassie, B., Jorgensen, N., Albers, E. L., Kemna, M. S., Soriano, B. D., Bhat, A. H., Kronmal, R. A., Bouccek, R. J., Law, Y. M. 2021: 1-8


    BACKGROUND: Longitudinal evaluation of allograft diastolic function in paediatric heart transplant recipients is important for early detection of acute rejection, cardiac allograft vasculopathy, and graft dysfunction. Mean diastolic right atrial and pulmonary capillary wedge pressures obtained at catheterisation are the reference standards for assessment. Echocardiography is non-invasive and more suitable for serial surveillance, but individual parameters have lacked accuracy. This study aimed to identify covariates of post-transplant mean right atrial and pulmonary capillary wedge pressures, including B-type natriuretic peptide and certain echocardiographic parameters.METHODS: A retrospective review of 143 scheduled cardiac catheterisations and echocardiograms from 56 paediatric recipients transplanted from 2007 to 2011 was performed. Samples with rejection were excluded. Univariate and multivariate linear regression models using backward selection were applied to a database consisting of B-type natriuretic peptide, haemodynamic, and echocardiographic data.RESULTS: Ln B-type natriuretic peptide, heart rate z-score, left ventricular end-diastolic dimension z-score, mitral E/e', and percent interventricular septal thickening in systole were independently associated with mean right atrial pressure. Ln B-type natriuretic peptide, heart rate z-score, left ventricular end-diastolic dimension z-score, left ventricular mass (observed/predicted), and mitral E/e' were independently associated with mean pulmonary capillary wedge pressure. Covariates of B-type natriuretic peptide included mean pulmonary artery and pulmonary capillary wedge pressures, height, haemoglobin, fractional shortening, percent interventricular septal thickening in systole, and pulmonary vascular resistance index.CONCLUSIONS: B-type natriuretic peptide and echocardiographic indices of diastolic function were independently related to post-transplant mean right atrial and pulmonary capillary wedge pressures in paediatric heart transplant recipients without rejection.

    View details for DOI 10.1017/S104795112100247X

    View details for PubMedID 34167609

  • Ultrasound education improves safety for peripheral intravenous catheter insertion in critically ill children. Pediatric research Bhargava, V., Su, E., Haileselassie, B., Davis, D., Steffen, K. M. 2021


    BACKGROUND: Difficulty in obtaining peripheral vascular access is a common problem in patients admitted to the pediatric intensive care unit (PICU). The use of ultrasound guidance can improve the overall success in obtaining vascular access. This study evaluated the success and longevity of PIV placement by nurses pre- and post-implementation of an USGPIV curriculum.METHODS: PICU nurses participated in a prospective quality improvement study. Each participating nurse attempted 10 PIVs by using landmark (LM) methods. The same nurses then received individual instruction in an USGPIV placement curriculum. Following the educational intervention, each nurse attempted 10 USGPIVs.RESULTS: A total of 150 LM PIVs and 143 USGPIVs were attempted. The first stick success in the post-intervention (USGPIV) group was 85.9% compared to 47.3% in the pre-intervention (LM) group (p<0.001). Overall success was also superior in the USGPIV group (94.3 versus 57.3%, respectively; p<0.001). PIVs placed by US lasted longer with a median survival time of 4±3.84 daysversus 3±3.51 days for LM PIVs (p<0.050, log-rank test).CONCLUSIONS: Successful implementation of a standardized curriculum for USGPIV placement for PICU nurses improves first stick, overall success, and longevity of PIV catheter placement.IMPACT: An ultrasound-guided IV curriculum can be successfully implemented resulting in increased first stick success and increased longevity. Registered nurses can be trained in placement of ultrasound-guided IV placement. This study provides a training curriculum for ultrasound-guided IV placement that can be applied to other settings or institutions.

    View details for DOI 10.1038/s41390-021-01568-6

    View details for PubMedID 34075190

  • The authors reply. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Bhargava, V., Haileselassie, B., Su, E. 2021; 22 (5): e331–e332

    View details for DOI 10.1097/PCC.0000000000002721

    View details for PubMedID 33953138

  • Assessment of Vocal Cord Motion Using Laryngeal Ultrasound in Children: A Systematic Review and Meta-Analysis. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Hamilton, C. E., Su, E. n., Tawfik, D. n., Fernandez, E. n., Veten, A. n., Conlon, T. n., Ginsburg, S. n., Mariano, K. n., Sidell, D. n., Haileselassie, B. n. 2021


    Laryngeal ultrasound is a nonirradiating, noninvasive method for assessing the upper airway in children. This systematic review and meta-analysis examine available evidence for accuracy of laryngeal ultrasound in diagnosing vocal cord immobility in infants and children after surgery and trauma affecting the vocal cords.Medical subject heading terms were used to search MEDLINE, Embase, Google Scholar, Web of Science, and the Cochrane Library for relevant citations. Publications from January 1, 2000, to June 30, 2020 were included in the search strategy. Study inclusion criteria consisted of randomized control trials and nonrandomized retrospective or prospective observational studies where vocal cord motion was evaluated by laryngeal ultrasound and compared with a reference test. Studies were excluded if there was insufficient data to compute a sensitivity/specificity table. Case reports, case series less than 10, and manuscripts not published in English were also excluded.Studies which included subjects younger than or equal to 18 years were considered for full article review.No restrictions on study settings were imposed in this systematic review.The initial search returned 1,357 citations. After de-duplication, abstract, and full review, eight citations were included in the final meta-analysis. A bivariate random-effects meta-analysis was performed, which revealed a pooled sensitivity for laryngeal ultrasound in detecting vocal cord immobility of 91% (95% CI, 83-95%), specificity of 97% (95% CI, 82-100%), diagnostic odds ratio 333.56 (95% CI, 34.00-3,248.71), positive likelihood ratio 31.58 (95% CI, 4.50-222.05), and negative likelihood ratio 0.09 (95% CI, 0.05-0.19).Laryngeal ultrasound demonstrates high sensitivity and specificity for detecting vocal cord motion in children in a wide range of clinical settings. Laryngeal ultrasound offers a low-risk imaging option for assessing vocal cord function in children compared with the current gold standard of laryngoscopy.

    View details for DOI 10.1097/PCC.0000000000002734

    View details for PubMedID 33833204

  • PhewWe Got the Kid BackNow What?: Understanding Risk Factors Which Contribute to In-Hospital Pediatric Recurrent Cardiac Arrest. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Haileselassie, B., Su, F., Berg, M. 2020; 21 (11): 1012–13

    View details for DOI 10.1097/PCC.0000000000002465

    View details for PubMedID 33136992

  • Characteristics of Pediatric Extracorporeal Membrane Oxygenation Programs in the United States and Canada. ASAIO journal (American Society for Artificial Internal Organs : 1992) Troy, L. n., Su, F. n., Kilbaugh, T. n., Rasmussen, L. n., Kuo, T. n., Jett, E. n., Cornell, T. n., Berg, M. n., Haileselassie, B. n. 2020


    The aim of this study was to evaluate the current infrastructure and practice characteristics of pediatric extracorporeal membrane oxygenation (ECMO) programs. A 40-question survey of center-specific demographics, practice structure, program experience, and support network utilized to cannulate and maintain a pediatric patient on ECMO was designed via a web-based survey tool. The survey was distributed to pediatric ECMO programs in the United States and Canada. Of the 101 centers that were identified to participate, 41 completed the survey. The majority of responding centers are university affiliated (73%) and have an intensive care unit (ICU) with 15-25 beds (58%). Extracorporeal membrane oxygenation has been offered for >10 years in 85% of the centers. The median number of total cannulations per center in 2017 was 15 (interquartile range [IQR] = 5-30), with the majority occurring in the cardiovascular intensive care unit (median = 13, IQR = 5-25). Fifty-seven percent of responding centers offer ECPR, with a median number of four cases per year (IQR = 2-7). Most centers cannulate in an operating room or ICU; 11 centers can cannulate in the pediatric ED. Sixty-three percent of centers have standardized protocols for postcannulation management. The majority of protocols guide anticoagulation, sedation, or ventilator management; left ventricle decompression and reperfusion catheter placement are the least standardized procedures. The majority of pediatric ECMO centers have adopted the infrastructure recommendations from the Extracorporeal Life Support Organization. However, there remains broad variability of practice characteristics and organizational infrastructure for pediatric ECMO centers across the United States and Canada.

    View details for DOI 10.1097/MAT.0000000000001311

    View details for PubMedID 33181543

  • Cardiac Dysfunction Identified by Strain Echocardiography Is Associated With Illness Severity in Pediatric Sepsis. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Patel, M. D., Mariano, K. n., Dunbar, T. n., Cornell, T. T., Punn, R. n., Haileselassie, B. n. 2020


    Sepsis-induced myocardial dysfunction has been associated with illness severity and mortality in pediatrics. Although early sepsis-induced myocardial dysfunction diagnosis could aid in hemodynamic management, current echocardiographic metrics for assessing biventricular function are limited in detecting early impairment. Strain echocardiography is a validated quantitative measure that can detect subtle perturbations in left ventricular and right ventricular function. This investigation evaluates the utility of strain echocardiography in pediatric sepsis and compares with to conventional methods.Retrospective, observational study comparing left ventricular and right ventricular strain. Strain was compared with ejection fraction and fractional shortening and established sepsis severity of illness markers.Tertiary care medical-surgical PICU from July 2013 to January 2018.Seventy-nine septic children and 28 healthy controls.None.Compared with healthy controls, patients with severe sepsis demonstrated abnormal left ventricular strain (left ventricular longitudinal strain: -13.0% ± 0.72; p = 0.04 and left ventricular circumferential strain: -16.5% ± 0.99; p = 0.046) and right ventricular (right ventricular longitudinal strain = -14.3% ± 6.3; p < 0.01) despite normal fractional shortening (36.0% ± 1.6 vs 38.1% ± 1.1; p = 0.5129) and ejection fraction (60.7% ± 2.2 vs 65.3% ± 1.5; p = 0.33). There was significant association between depressed left ventricular longitudinal strain and increased Vasotrope-Inotrope Score (r = 0.52; p = 0.034). Worsening left ventricular circumferential strain was correlated with higher lactate (r = 0.31; p = 0.03) and higher Pediatric Risk of Mortality-III score (r = 0.39; p < 0.01). Depressed right ventricular longitudinal strain was associated with elevated pediatric multiple organ dysfunction score (r = 0.44; p < 0.01) CONCLUSIONS:: Compared with healthy children, pediatric septic patients demonstrated abnormal left ventricular and right ventricular strain concerning for early signs of cardiac dysfunction. This was despite having normal ejection fraction and fractional shortening. Abnormal strain was associated with abnormal severity of illness markers. Strain echocardiography may have utility as an early indicator of sepsis-induced myocardial dysfunction in pediatric sepsis.

    View details for DOI 10.1097/PCC.0000000000002247

    View details for PubMedID 32084099

  • Predicting Mortality in Children With Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study. Critical care medicine Yehya, N. n., Harhay, M. O., Klein, M. J., Shein, S. L., Piñeres-Olave, B. E., Izquierdo, L. n., Sapru, A. n., Emeriaud, G. n., Spinella, P. C., Flori, H. R., Dahmer, M. K., Maddux, A. B., Lopez-Fernandez, Y. M., Haileselassie, B. n., Hsing, D. D., Chima, R. S., Hassinger, A. B., Valentine, S. L., Rowan, C. M., Kneyber, M. C., Smith, L. S., Khemani, R. G., Thomas, N. J. 2020


    Pediatric acute respiratory distress syndrome is heterogeneous, with a paucity of risk stratification tools to assist with trial design. We aimed to develop and validate mortality prediction models for patients with pediatric acute respiratory distress syndrome.Leveraging additional data collection from a preplanned ancillary study (Version 1) of the multinational Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology study, we identified predictors of mortality. Separate models were built for the entire Version 1 cohort, for the cohort excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths. Models were externally validated in a cohort of intubated pediatric acute respiratory distress syndrome patients from the Children's Hospital of Philadelphia.The derivation cohort represented 100 centers worldwide; the validation cohort was from Children's Hospital of Philadelphia.There were 624 and 640 subjects in the derivation and validation cohorts, respectively.None.The model for the full cohort included immunocompromised status, Pediatric Logistic Organ Dysfunction 2 score, day 0 vasopressor-inotrope score and fluid balance, and PaO2/FIO2 6 hours after pediatric acute respiratory distress syndrome onset. This model had good discrimination (area under the receiver operating characteristic curve 0.82), calibration, and internal validation. Models excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths also demonstrated good discrimination (all area under the receiver operating characteristic curve ≥ 0.84) and calibration. In the validation cohort, models for intubated pediatric acute respiratory distress syndrome (including and excluding neurologic deaths) had excellent discrimination (both area under the receiver operating characteristic curve ≥ 0.85), but poor calibration. After revision, the model for all intubated subjects remained miscalibrated, whereas the model excluding neurologic deaths showed perfect calibration. Mortality models also stratified ventilator-free days at 28 days in both derivation and validation cohorts.We describe predictive models for mortality in pediatric acute respiratory distress syndrome using readily available variables from day 0 of pediatric acute respiratory distress syndrome which outperform severity of illness scores and which demonstrate utility for composite outcomes such as ventilator-free days. Models can assist with risk stratification for clinical trials.

    View details for DOI 10.1097/CCM.0000000000004345

    View details for PubMedID 32271186

  • Ultrasonographic Optic Nerve Sheath Diameter Measurement to Detect Intracranial Hypertension in Children With Neurological Injury: A Systematic Review. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Bhargava, V. n., Tawfik, D. n., Tan, Y. J., Dunbar, T. n., Haileselassie, B. n., Su, E. n. 2020


    Ultrasound measured optic nerve sheath diameter is a noninvasive, nonirradiating tool for estimating intracranial hypertension. The objective of this systematic review and meta-analysis is summarization of the current evidence for accuracy of ultrasound measured optic nerve sheath diameter in detecting intracranial hypertension in pediatric patients.Medical subject heading terms were used to search MEDLINE, Embase, Google Scholar, Web of Science, and the Cochrane Library for relevant citations. Publications from January 1, 2000, to June 30, 2019, were included in the search strategy.Studies were included if they involved patients less than 18 years, where ultrasound measured optic nerve sheath diameter was compared to conventional, nonophthalmic tests for intracranial hypertension. Studies were excluded if there was insufficient data to compute a sensitivity/specificity table. Case reports, case series, and manuscripts not published in English were also excluded.The initial search returned 573 citations. Of these, 57 were selected for review.Eleven citations were included in the final meta-analysis. A bivariate random-effects meta-analysis was performed, which revealed a pooled sensitivity for ultrasound measured optic nerve sheath diameter of 93% (95% CI, 74-99%), a specificity of 74% (95% CI, 52-88%), and a diagnostic odds ratio of 39.00 (95% CI, 4.16-365.32). The area under the curve of the hierarchical summary receiver operating characteristic curve was 0.90 (95% CI, 0.87-0.93). Subgroup analyses of the test's performance evaluating new-onset intracranial hypertension and in comparison to invasively measured intracranial pressure were performed. The test performance in these instances was similar to findings in the primary analysis.We are unable to identify a threshold value in ultrasound measured optic nerve sheath diameter for the determination of intracranial hypertension in children. Even though the ultrasound measured optic nerve sheath diameter measurement is highly sensitive to the presence of increased intracranial pressure, the test has only moderate specificity. Therefore, other confirmatory methods and further investigation is necessary in the clinical care of children. The technique is likely not sufficiently precise for clinical use in the absence of other confirmatory methods, and further investigation is necessary to determine clinical protocols for its use in children.

    View details for DOI 10.1097/PCC.0000000000002453

    View details for PubMedID 32796395

  • Early Use of Adjunctive Therapies for Pediatric Acute Respiratory Distress Syndrome: A PARDIE Study. American journal of respiratory and critical care medicine Rowan, C. M., Klein, M. J., Hsing, D. D., Dahmer, M. K., Spinella, P. C., Emeriaud, G. n., Hassinger, A. B., Piñeres-Olave, B. E., Flori, H. R., Haileselassie, B. n., Lopez-Fernandez, Y. M., Chima, R. S., Shein, S. L., Maddux, A. B., Lillie, J. n., Kneyber, M. C., Smith, L. S., Khemani, R. G., Thomas, N. J., Yehya, N. n. 2020


    Little data exist to guide early adjunctive therapy use in pediatric acute respiratory distress syndrome (PARDS).To describe contemporary use of adjunctive therapies for early PARDS as a framework for future investigations.Pre-planned, sub-study of a prospective, international, cross-sectional observational study of children with PARDS from 100 centers over 10 study weeks.We investigated six adjunctive therapies for PARDS: continuous neuromuscular blockade (cNMB), corticosteroids, inhaled nitric oxide (iNO), prone positioning, high frequency oscillatory ventilation (HFOV), and extracorporeal membrane oxygenation (ECMO). Almost half (45%) of children with PARDS received at least one therapy. Variability was noted in the median starting oxygenation index (OI) of each therapy; corticosteroids started at the lowest OI (13.0 IQR:7.6, 22.0) and HFOV at the highest (25.7 IQR:16.7, 37.3). Continuous NMB was the most common, used in 31%, followed by iNO (13%), corticosteroids (10%), prone positioning (10%), HFOV (9%), and ECMO (3%). Steroids, iNO, and HFOV were associated with comorbidities. Prone positioning and HFOV were more common in middle-income countries and less frequently used in North America. The use of multiple ancillary therapies increased over the first 3 days of PARDS, but there was not an easily identifiable pattern of combination or order of use.The contemporary description of prevalence, combinations of therapies and oxygenation threshold for which the therapies are applied is important for design of future studies. Region of the world, income and comorbidities influence adjunctive therapy use and are important variables to include in PARDS investigations.

    View details for DOI 10.1164/rccm.201909-1807OC

    View details for PubMedID 32130867

  • Regulating Critical Care Ultrasound, It Is All in the Interpretation. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Su, E. n., Soni, N. J., Blaivas, M. n., Bhargava, V. n., Steffen, K. n., Haileselassie, B. n. 2020


    Point-of-care ultrasound (POCUS) use is rapidly expanding as a practice in adult and pediatric critical care environments. In January 2020, the Joint Commission endorsed a statement from the Emergency Care Research Institute citing point-of-care ultrasound as a potential hazard to patients for reasons related to training and skill verification, oversight of use, and recordkeeping and accountability mechanisms for clinical use; however, no evidence was presented to support these concerns. Existing data on point-of-care ultrasound practices in pediatric critical care settings verify that point-of-care ultrasound use continues to increase, and contrary to the concerns raised, resources are becoming increasingly available for point-of-care ultrasound use. Many institutions have recognized a successful approach to addressing these concerns that can be achieved through multispecialty collaborations.

    View details for DOI 10.1097/PCC.0000000000002600

    View details for PubMedID 33060421

  • PERSEVERE Biomarkers Predict Severe Acute Kidney Injury and Renal Recovery in Pediatric Septic Shock. American journal of respiratory and critical care medicine Stanski, N. L., Stenson, E. K., Cvijanovich, N. Z., Weiss, S. L., Fitzgerald, J. C., Bigham, M. T., Jain, P. N., Schwarz, A. n., Lutfi, R. n., Nowak, J. n., Allen, G. L., Thomas, N. J., Grunwell, J. R., Baines, T. n., Quasney, M. n., Haileselassie, B. n., Wong, H. R. 2020


    Acute kidney injury (AKI), a common complication of sepsis, is associated with substantial morbidity and mortality and lacks definitive disease-modifying therapy. Early, reliable identification of at risk patients is important for targeted implementation of renal protective measures. PERSEVERE-II is a validated, multi-biomarker prognostic enrichment strategy to estimate baseline mortality risk in pediatric septic shock.To assess the association between PERSEVERE-II mortality probability and the development of severe, sepsis-associated AKI on day 3 (D3 SA-AKI) in pediatric septic shock.Secondary analysis of a prospective, observational study of children with septic shock in whom the PERSEVERE biomarkers were measured to assign a PERSEVERE-II baseline mortality risk.Among 379 patients, 65 (17%) developed severe D3 SA-AKI. The proportion of patients developing severe D3 SA-AKI increased directly with increasing PERSEVERE-II risk category, and increasing PERSEVERE-II mortality probability was independently associated with increased odds of severe D3 SA-AKI after adjustment for age and illness severity (OR 1.4, 95% CI: 1.2-1.7, p<0.001). Similar associations were found between increasing PERSEVERE-II mortality probability and the need for renal replacement therapy. Lower PERSEVERE-II mortality probability was independently associated with increased odds of renal recovery among patients with early AKI. A newly derived model incorporating the PERSEVERE biomarkers and day 1 AKI status predicted severe D3 SA-AKI with an AUROC of 0.95 (95% CI: 0.92 to 0.98).Among children with septic shock, the PERSEVERE biomarkers predict severe D3 SA-AKI and identify patients with early AKI who are likely to recover.

    View details for DOI 10.1164/rccm.201911-2187OC

    View details for PubMedID 31916857

  • Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood brain barrier in septic encephalopathy. Journal of neuroinflammation Haileselassie, B. n., Joshi, A. U., Minhas, P. S., Mukherjee, R. n., Andreasson, K. I., Mochly-Rosen, D. n. 2020; 17 (1): 36


    Out of the myriad of complications associated with septic shock, septic-associated encephalopathy (SAE) carries a significant risk of morbidity and mortality. Blood-brain-barrier (BBB) impairment, which subsequently leads to increased vascular permeability, has been associated with neuronal injury in sepsis. Thus, preventing BBB damage is an attractive therapeutic target. Mitochondrial dysfunction is an important contributor of sepsis-induced multi-organ system failure. More recently, mitochondrial dysfunction in endothelial cells has been implicated in mediating BBB failure in stroke, multiple sclerosis and in other neuroinflammatory disorders. Here, we focused on Drp1-mediated mitochondrial dysfunction in endothelial cells as a potential target to prevent BBB failure in sepsis.We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in a cell culture as well as in murine model of sepsis. BBB disruption was assessed by measuring levels of key tight-junction proteins. Brain cytokines levels, oxidative stress markers, and activity of mitochondrial complexes were measured using biochemical assays. Astrocyte and microglial activation were measured using immunoblotting and qPCR. Transwell cultures of brain microvascular endothelial cells co-cultured with astrocytes were used to assess the effect of LPS on expression of tight-junction proteins, mitochondrial function, and permeability to fluorescein isothiocyanate (FITC) dextran. Finally, primary neuronal cultures exposed to LPS were assessed for mitochondrial dysfunction.LPS induced a strong brain inflammatory response and oxidative stress in mice which was associated with increased Drp1 activation and mitochondrial localization. Particularly, Drp1-(Fission 1) Fis1-mediated oxidative stress also led to an increase in expression of vascular permeability regulators in the septic mice. Similarly, mitochondrial defects mediated via Drp1-Fis1 interaction in primary microvascular endothelial cells were associated with increased BBB permeability and loss of tight-junctions after acute LPS injury. P110, an inhibitor of Drp1-Fis1 interaction, abrogated these defects, thus indicating a critical role for this interaction in mediating sepsis-induced brain dysfunction. Finally, LPS mediated a direct toxic effect on primary cortical neurons, which was abolished by P110 treatment.LPS-induced impairment of BBB appears to be dependent on Drp1-Fis1-mediated mitochondrial dysfunction. Inhibition of mitochondrial dysfunction with P110 may have potential therapeutic significance in septic encephalopathy.

    View details for DOI 10.1186/s12974-019-1689-8

    View details for PubMedID 31987040

  • Western diet regulates immune status and the response to LPS-driven sepsis independent of diet-associated microbiome. Proceedings of the National Academy of Sciences of the United States of America Napier, B. A., Andres-Terre, M., Massis, L. M., Hryckowian, A. J., Higginbottom, S. K., Cumnock, K., Casey, K. M., Haileselassie, B., Lugo, K. A., Schneider, D. S., Sonnenburg, J. L., Monack, D. M. 2019; 116 (9): 3688–94


    Sepsis is a deleterious immune response to infection that leads to organ failure and is the 11th most common cause of death worldwide. Despite plaguing humanity for thousands of years, the host factors that regulate this immunological response and subsequent sepsis severity and outcome are not fully understood. Here we describe how the Western diet (WD), a diet high in fat and sucrose and low in fiber, found rampant in industrialized countries, leads to worse disease and poorer outcomes in an LPS-driven sepsis model in WD-fed mice compared with mice fed standard fiber-rich chow (SC). We find that WD-fed mice have higher baseline inflammation (metaflammation) and signs of sepsis-associated immunoparalysis compared with SC-fed mice. WD mice also have an increased frequency of neutrophils, some with an "aged" phenotype, in the blood during sepsis compared with SC mice. Importantly, we found that the WD-dependent increase in sepsis severity and higher mortality is independent of the microbiome, suggesting that the diet may be directly regulating the innate immune system through an unknown mechanism. Strikingly, we could predict LPS-driven sepsis outcome by tracking specific WD-dependent disease factors (e.g., hypothermia and frequency of neutrophils in the blood) during disease progression and recovery. We conclude that the WD is reprogramming the basal immune status and acute response to LPS-driven sepsis and that this correlates with alternative disease paths that lead to more severe disease and poorer outcomes.

    View details for PubMedID 30808756

  • ROLE OF DRP1/FIS1-MEDIATED MITOCHONDRIAL FRAGMENTATION IN SEPSIS-INDUCED MYOCARDIAL DYSFUNCTION Haileselassie, B., Joshi, A., Mukherjee, R., Napier, B., Massis, L., Ostberg, N., Monack, D., Bernstein, D., Mochly-Rosen, D. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nature neuroscience Joshi, A. U., Minhas, P. S., Liddelow, S. A., Haileselassie, B. n., Andreasson, K. I., Dorn, G. W., Mochly-Rosen, D. n. 2019; 22 (10): 1635–48


    In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.

    View details for DOI 10.1038/s41593-019-0486-0

    View details for PubMedID 31551592

  • Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model. Science translational medicine Wong, H. R., Caldwell, J. T., Cvijanovich, N. Z., Weiss, S. L., Fitzgerald, J. C., Bigham, M. T., Jain, P. N., Schwarz, A. n., Lutfi, R. n., Nowak, J. n., Allen, G. L., Thomas, N. J., Grunwell, J. R., Baines, T. n., Quasney, M. n., Haileselassie, B. n., Lindsell, C. J. 2019; 11 (518)


    Sepsis remains a major public health problem with no major therapeutic advances over the last several decades. The clinical and biological heterogeneity of sepsis have limited success of potential new therapies. Accordingly, there is considerable interest in developing a precision medicine approach to inform more rational development, testing, and targeting of new therapies. We previously developed the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate mortality risk and proposed its use as a prognostic enrichment tool in sepsis clinical trials; prognostic enrichment selects patients based on mortality risk independent of treatment. Here, we show that PERSEVERE has excellent performance in a diverse cohort of children with septic shock with potential for use as a predictive enrichment strategy; predictive enrichment selects patients based on likely response to treatment. We demonstrate that the PERSEVERE biomarkers are reliably associated with mortality in mice challenged with experimental sepsis, thus providing an opportunity to test precision medicine strategies in the preclinical setting. Using this model, we tested two clinically feasible therapeutic strategies, guided by the PERSEVERE-based enrichment, and found that mice identified as high risk for mortality had a greater bacterial burden and could be rescued by higher doses of antibiotics. The association between higher pathogen burden and higher mortality risk was corroborated among critically ill children with septic shock. This bedside to bench to bedside approach provides proof of principle for PERSEVERE-guided application of precision medicine in sepsis.

    View details for DOI 10.1126/scitranslmed.aax9000

    View details for PubMedID 31723040

  • Drp1/Fis1 interaction mediates mitochondrial dysfunction in septic cardiomyopathy. Journal of molecular and cellular cardiology Haileselassie, B. n., Mukherjee, R. n., Joshi, A. U., Napier, B. A., Massis, L. M., Ostberg, N. P., Queliconi, B. B., Monack, D. n., Bernstein, D. n., Mochly-Rosen, D. n. 2019


    Mitochondrial dysfunction is a key contributor to septic cardiomyopathy. Although recent literature implicates dynamin related protein 1 (Drp1) and its mitochondrial adaptor fission 1 (Fis1) in the development of pathologic fission and mitochondrial failure in neurodegenerative disease, little is known about the role of Drp1/Fis1 interaction in the context of sepsis-induced cardiomyopathy. Our study tests the hypothesis that Drp1/Fis1 interaction is a major driver of sepsis-mediated pathologic fission, leading to mitochondrial dysfunction in the heart.H9C2 cardiomyocytes were treated with lipopolysaccharide (LPS) to evaluate changes in mitochondrial membrane potential, oxidative stress, cellular respiration, and mitochondrial morphology. Balb/c mice were treated with LPS, cardiac function was measured by echocardiogaphy, and mitochondrial morphology determined by electron microscopy (EM). Drp1/Fis1 interaction was inhibited by P110 to determine whether limiting mitochondrial fission can reduce LPS-induced oxidative stress and cardiac dysfunction.LPS-treated H9C2 cardiomyocytes demonstrated a decrease in mitochondrial respiration followed by an increase in mitochondrial oxidative stress and a reduction in membrane potential. Inhibition of Drp1/Fis1 interaction with P110 attenuated LPS-mediated cellular oxidative stress and preserved membrane potential. In vivo, cardiac dysfunction in LPS-treated mice was associated with increased mitochondrial fragmentation. Treatment with P110 reduced cardiac mitochondrial fragmentation, prevented decline in cardiac function, and reduced mortality.Sepsis decreases cardiac mitochondrial respiration and membrane potential while increasing oxidative stress and inducing pathologic fission. Treatment with P110 was protective in both in vitro and in vivo models of septic cardiomyopathy, suggesting a key role of Drp1/Fis1 interaction, and a potential target to reduce its morbidity and mortality.

    View details for PubMedID 30981733

  • Low Left Atrial Strain Is Associated With Adverse Outcomes in Hypertrophic Cardiomyopathy Patients. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography Vasquez, N. n., Ostrander, B. T., Lu, D. Y., Ventoulis, I. n., Haileselassie, B. n., Goyal, S. n., Greenland, G. V., Vakrou, S. n., Olgin, J. E., Abraham, T. P., Abraham, M. R. 2019


    Paroxysmal atrial fibrillation (PAF) and left atrial (LA) structural remodeling are common in hypertrophic cardiomyopathy (HCM) patients, who are also at risk for adverse cardiovascular outcomes.We assessed whether PAF and/or LA remodeling was associated with adverse outcomes in HCM.We retrospectively studied 45 HCM patients with PAF (PAF group) and 59 HCM patients without atrial fibrillation (AF; no-AF group). LA/left ventricular (LV) function and mechanics were assessed by echocardiography. Patients were followed for development of the composite endpoint comprising heart failure, stroke, and death.Clinical/demographic characteristics, degree of LV hypertrophy, and E/e' were similar in the two groups The PAF group had significantly higher LA volume, but lower LA ejection fraction (LAEF), LA contractile, and reservoir strain/strain rate than the no-AF group. During follow-up, 27 patients developed the composite endpoint. Incidence of the composite endpoint was similar in the two groups. Absolute values of 23.8% for reservoir strain and 10.2% for conduit strain were the best cutoffs for the composite endpoint, using receiver operating characteristic analysis. Kaplan-Meier survival analysis showed lower event-free survival in patients with reservoir strain ≤23.8% or conduit strain ≤10.2%. Univariate Cox analysis revealed an association between female sex, LAEF, LA reservoir/conduit strain, and LV global longitudinal strain with the composite endpoint. The association between LA reservoir/conduit strain and the composite endpoint persisted after controlling for age, sex, LAEF, and LV global longitudinal strain.In this pilot HCM patient study, PAF was associated with a greater degree of LA myopathy, and low LA reservoir and conduit strain were associated with higher risk for adverse cardiovascular outcomes.

    View details for PubMedID 30904367

  • Deciphering the Effects of Performing Ultrasound on Critically Ill Emergency Department Patients Critical Care Explorations Bhargava, V., Haileselassie, B., Su, E. 2019
  • Interaction of mitochondrial fission factor with dynamin related protein 1 governs physiological mitochondrial function in vivo. Scientific reports Kornfeld, O. S., Qvit, N., Haileselassie, B., Shamloo, M., Bernardi, P., Mochly-Rosen, D. 2018; 8 (1): 14034


    Mitochondria form a dynamic network governed by a balance between opposing fission and fusion processes. Because excessive mitochondrial fission correlates with numerous pathologies, including neurodegeneration, the mechanism governing fission has become an attractive therapeutic strategy. However, targeting fission is a double-edged sword as physiological fission is necessary for mitochondrial function. Fission is trigged by Drp1 anchoring to adaptors tethered to the outer mitochondrial membrane. We designed peptide P259 that distinguishes physiological from pathological fission by specifically inhibiting Drp1's interaction with the Mff adaptor. Treatment of cells with P259 elongated mitochondria and disrupted mitochondrial function and motility. Sustained in vivo treatment caused a decline in ATP levels and altered mitochondrial structure in the brain, resulting in behavioral deficits in wild-type mice and a shorter lifespan in a mouse model of Huntington's disease. Therefore, the Mff-Drp1 interaction is critical for physiological mitochondrial fission, motility, and function in vitro and in vivo. Tools, such as P259, that differentiate physiological from pathological fission will enable the examination of context-dependent roles of Drp1 and the suitability of mitochondrial fission as a target for drug development.

    View details for PubMedID 30232469

  • Drp1/Fis1-mediated mitochondrial fragmentation leads to lysosomal dysfunction in cardiac models of Huntington's disease. Journal of molecular and cellular cardiology Joshi, A. U., Ebert, A. E., Haileselassie, B. n., Mochly-Rosen, D. n. 2018; 127: 125–33


    Huntington's disease (HD) is a fatal hereditary neurodegenerative disorder, best known for its clinical triad of progressive motor impairment, cognitive deficits and psychiatric disturbances, is caused by CAG-repeat expansion in exon 1 of Huntingtin (HTT). However, in addition to the neurological disease, mutant HTT (mHTT), which is ubiquitously expressed in all tissues, impairs other organ systems. Not surprisingly, cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with HD. Mitochondrial dysfunction in the brain and skeletal muscle in HD has been well documented, as the disease progresses. However, not much is known about mitochondrial abnormalities in the heart. In this study, we describe a role for Drp1/Fis1-mediated excessive mitochondrial fission and dysfunction, associated with lysosomal dysfunction in H9C2 expressing long polyglutamine repeat (Q73) and in human iPSC-derived cardiomyocytes transfected with Q77. Expression of long polyglutamine repeat led to reduced ATP production and mitochondrial fragmentation. We observed an increased accumulation of damaged mitochondria in the lysosome that was coupled with lysosomal dysfunction. Importantly, reducing Drp1/Fis1-mediated mitochondrial damage significantly improved mitochondrial function and cell survival. Finally, reducing Fis1-mediated Drp1 recruitment to the mitochondria, using the selective inhibitor of this interaction, P110, improved mitochondrial structure in the cardiac tissue of R6/2 mice. We suggest that drugs focusing on the central nervous system will not address mitochondrial function across all organs, and therefore will not be a sufficient strategy to treat or slow down HD disease progression.

    View details for DOI 10.1016/j.yjmcc.2018.12.004

    View details for PubMedID 30550751

  • Diagnostic Bedside Ultrasound Program Development in Pediatric Critical Care Medicine: Results of a National Survey. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Conlon, T. W., Kantor, D. B., Su, E. R., Basu, S. n., Boyer, D. L., Haileselassie, B. n., Petersen, T. L., Su, F. n., Nishisaki, A. n. 2018


    To assess current diagnostic bedside ultrasound program core element (training, credentialing, image storage, documentation, and quality assurance) implementation across pediatric critical care medicine divisions in the United States.Cross-sectional questionnaire-based needs assessment survey.Pediatric critical care medicine divisions with an Accreditation Council of Graduate Medical Education-accredited fellowship.Divisional leaders in education and/or bedside ultrasound training.None.Fifty-five of 67 pediatric critical care medicine divisions (82%) with an Accreditation Council of Graduate Medical Education-accredited fellowship provided responses. Overall, 63% of responding divisions (34/54) were clinically performing diagnostic bedside ultrasound studies with no difference between divisions with large versus small units. Diagnostic bedside ultrasound training is available for pediatric critical care medicine fellows within 67% of divisions (35/52) with no difference in availability between divisions with large versus small units. Other core elements were present in less than 25% of all divisions performing clinical studies, with a statistically significant increase in credentialing and documentation among divisions with large units (p = 0.048 and 0.01, respectively). All core elements were perceived to have not only high impact in program development but also high effort in implementation. Assuming that all structural elements could be effectively implemented within their division, 83% of respondents (43/52) agreed that diagnostic bedside ultrasound should be a core curricular component of fellowship education.Diagnostic bedside ultrasound is increasingly prevalent in training and clinical use across the pediatric critical care medicine landscape despite frequently absent core programmatic infrastructural elements. These core elements are perceived as important to program development, regardless of division unit size. Shared standardized resources may assist in reducing the effort in core element implementation and allow us to measure important educational and clinical outcomes.

    View details for PubMedID 30113518

  • Certification in Critical Care Echocardiography: The Evolution of an Emerging PICU Practice PEDIATRIC CRITICAL CARE MEDICINE Su, E., Haileselassie, B., Hernandez, A., Diaz-Gomez, J. L. 2018; 19 (1): 88

    View details for PubMedID 29303901

  • E/e' ratio and outcome prediction in hypertrophic cardiomyopathy: the influence of outflow tract obstruction. European heart journal cardiovascular Imaging Lu, D. Y., Haileselassie, B., Ventoulis, I., Liu, H. Y., Liang, H. Y., Pozios, I., Canepa, M., Phillip, S., Abraham, M. R., Abraham, T. 2018; 19 (1): 101-107


    Diastolic dysfunction is thought to be an important pathophysiologic component of hypertrophic cardiomyopathy (HCM). However, there are conflicting data on the potential value of the mitral E/e' ratio. We examined whether left ventricular outflow tract (LVOT) obstruction influences the value of E/e' in predicting outcomes in HCM.Patients who met diagnostic criteria for HCM were enrolled. Diastolic function was assessed with complete two-dimensional and Doppler echocardiography. A composite clinical outcome including new onset atrial fibrillation, sustained ventricular tachycardia/fibrillation, heart failure, transplantation, and death was examined over a mean follow-up period of 4.2 years. Among 604 patients, 206 patients had an E/e' level ≥20. Patients with higher septal E/e' level were older, with more severe NYHA class, and more severe LVOT obstruction. Higher E/e' was associated with worse event-free survival in non-obstructive group and total HCM cohort. In addition, E/e' and LVOT pressure gradient were highly correlated in non-obstructive and total HCM, but not in labile or obstructive group. During follow-up period, 95 patients underwent myectomy. Post-op E/e' correlated significantly with LVOT pressure gradient (R = 0.306, P = 0.004). In these patients, post-op E/e' was associated with worse event-free survival (log-rank P = 0.030).Assessment of E/e' is useful for risk stratification in HCM patients. Nevertheless, the predictive power is confounded by dynamic LVOT obstruction. Higher E/e' predicts worse clinical outcomes in non-obstructive HCM and in labile/obstructive after myectomy.

    View details for DOI 10.1093/ehjci/jex134

    View details for PubMedID 28977350

  • Certification in Critical Care Echocardiography: The Evolution of an Emerging PICU Practice. Pediatr Crit Care Med. Su, E., Haileselassie, B., Hernandez, A., Díaz-Gómez, J. L. 2018 ; 19 ((1))
  • Clinical Outcomes in Patients With Nonobstructive, Labile, and Obstructive Hypertrophic Cardiomyopathy. Journal of the American Heart Association Lu, D., Pozios, I., Haileselassie, ., Ventoulis, I., Liu, H., Sorensen, L., Canepa, M., Phillip, S., Abraham, R. M., Abraham, T. P. 2018: e006657.

    View details for DOI 10.1161/JAHA.117.006657.

  • Myocardial oxidative stress correlates with left ventricular dysfunction on strain echocardiography in a rodent model of sepsis. Intensive care medicine experimental Haileselassie, B., Su, E., Pozios, I., Niño, D. F., Liu, H., Lu, D., Ventoulis, I., Fulton, W. B., Sodhi, C. P., Hackam, D., O'Rourke, B., Abraham, T. 2017; 5 (1): 21-?


    Recognition of cardiomyopathy in sepsis can be challenging due to the limitations of conventional measures such as ejection fraction (EF) and fractional shortening (FS) in the context of variable preload and afterload conditions. This study correlates myocardial function using strain echocardiography (SE) with cardiomyocyte oxidative stress in a murine model of sepsis.C57BL/6J mice were randomized into control (n = 10), sham (n = 25), and a cecal ligation and puncture (CLP) (n = 33) model of sepsis. Echocardiography was performed pre-, 12, 24, and 48 h post-injury. Cardiac pro-inflammatory cytokines and mitochondrial redox scavenger expression were evaluated in a subset of each arm. To evaluate the influence of redox scavenger upregulation on oxidative injury and cardiac function, CLP was performed on mitochondrial catalase-upregulated C57BL/6J MCAT(+/+) mice (n = 12) and wild-type (WT) animals for comparison.Septic C57BL/6J mice exhibited depressed longitudinal strain (LS) when compared to sham and control at 24 h (p < 0.01) and 48 h (p = 0.04) post-CLP despite having a preserved EF. Furthermore, there was a significant association between increased odds of mortality and depressed LS (OR = 1.23, p = 0.04). Septic C57BL/6J mice concomitantly demonstrated increased expression of cardiomyocyte pro-inflammatory cytokines and decreased expression of redox scavengers at 24 and 48 h. When comparing C57Bl/6 MCAT (+/+) mice and C57BL/6J WT mice, a significant decrease in LS was identified in the WT mice at 24 h (MCAT = -23 ± 5% vs. WT = -15 ± 4% p < 0.01) and 48 h (MCAT = -23 ± 7% vs. WT = -15 ± 4.3% p = 0.04) post-CLP which correlated with significant increase in the level of cardiac oxidative stress following CLP.In this sepsis model, SE identified cardiomyopathy despite normal EF. SE depression temporally coincides with upregulation of inflammatory cytokines and decreases expression of key mitochondrial ROS scavengers. Upregulation of redox scavenger (CAT) abrogates oxidative stress and cardiac dysfunction in this sepsis model.

    View details for DOI 10.1186/s40635-017-0134-5

    View details for PubMedID 28405943

  • Impact of peak provoked left ventricular outflow tract gradients on clinical outcomes in hypertrophic cardiomyopathy. International journal of cardiology Lu, D. Y., Hailesealassie, B., Ventoulis, I., Liu, H., Liang, H. Y., Nowbar, A., Pozios, I., Canepa, M., Cresswell, K., Luo, H. C., Abraham, M. R., Abraham, T. P. 2017; 243: 290-295


    Hypertrophic cardiomyopathy (HCM) is traditionally classified based on a left ventricular outflow tract (LVOT) pressure gradient of 30mmHg at rest or with provocation. There are no data on whether 30mmHg is the most informative cut-off value and whether provoked gradients offer any information regarding outcomes.Resting and provoked peak LVOT pressure gradients were measured by Doppler echocardiography in patients fulfilling guidelines criteria for HCM. A composite clinical outcome including new onset atrial fibrillation, ventricular tachycardia/fibrillation, heart failure, transplantation, and death was examined over a median follow-up period of 2.1years.Among 536 patients, 131 patients had resting LVOT gradients greater than 30mmHg. Subjects with higher resting gradients were older with more cardiovascular events. For provoked gradients, a bi-modal risk distribution was found. Patients with provoked gradients >90mmHg (HR 3.92, 95% CI 1.97-7.79) or <30mmHg (HR 2.15, 95% CI 1.08-4.29) have more events compared to those with gradients between 30 and 89mmHg in multivariable analysis. The introduction of two cut-off points for provoked gradients allowed HCM to be reclassified into four groups: patients with "benign" latent HCM (provoked gradient 30-89mmHg) had the best prognosis, whereas those with persistent obstructive HCM had the worst outcome.Provoked LVOT pressure gradients offer additional information regarding clinical outcomes in HCM. Applying cut-off points at 30 and 90mmHg to provoked LVOT pressure gradients further classifies HCM patients into low-, intermediate- and high-risk groups.

    View details for DOI 10.1016/j.ijcard.2017.04.039

    View details for PubMedID 28747034

  • Role of Global Longitudinal Strain in Predicting Outcomes in Hypertrophic Cardiomyopathy. The American journal of cardiology Liu, H., Pozios, I., Haileselassie, B., Nowbar, A., Sorensen, L. L., Phillip, S., Lu, D. Y., Ventoulis, I., Luo, H., Abraham, M. R., Abraham, T. P. 2017; 120 (4): 670-675


    Global longitudinal strain (GLS) is a sensitive indicator of global left ventricular function particularly in those with normal ejection fraction. We examined the potential value of GLS in predicting outcomes in hypertrophic cardiomyopathy (HC). Conventional and strain echocardiography was performed in 400 patients with HC followed for a median 3.1 years (interquartile range 1.2 to 5.6). Peak systolic strain from 3 apical views was averaged to calculate GLS. Patients were divided based on a previously published cutoff value of -16%. Additionally, we identified 4 HC subgroups based on GLS: GLS ≤ -20%, -20% < GLS ≤ -16%, -16% < GLS ≤ -10%, and GLS > -10%. The primary end point was a composite of new-onset sustained ventricular tachycardia/fibrillation, heart failure, cardiac transplantation, and all-cause death. Patients with GLS > -16% had significantly more events (17% vs 7%, p = 0.002). In the 4-group analysis, event rates increased with worsening GLS (5%, 7%, 14%, and 33%, respectively, p = 0.001). Event-free survival was significantly superior in those with GLS ≤ -16% versus GLS > -16% (p = 0.004); similarly, GLS > -10% portended a significantly worse event-free survival compared with each of the other 3 groups (p <0.01 for all pairwise comparisons). By univariate and multivariate Cox regression analysis, GLS remained significantly associated with the composite end point. GLS > -10% had 4 times the risk of events compared with GLS ≤ -16% (p = 0.006). In conclusion, echo-based GLS is independently associated with outcomes in HC. Patients with GLS > -10% have significantly higher event rates.

    View details for DOI 10.1016/j.amjcard.2017.05.039

    View details for PubMedID 28687124

  • Strain Echocardiography Parameters Correlate With Disease Severity in Children and Infants With Sepsis PEDIATRIC CRITICAL CARE MEDICINE Haileselassie, B., Su, E., Pozios, I., Fiskum, T., Thompson, R., Abraham, T. 2016; 17 (5): 383-390


    In the progression of severe sepsis, sepsis-induced myocardial dysfunction contributes to severity of illness and ultimate mortality. Identification of sepsis-induced myocardial dysfunction causing depressed cardiac function during critical illness has implications for ongoing patient management. However, assessing pediatric cardiac function traditionally relies on echocardiographic qualitative assessment and measurement of left ventricular ejection fraction or fractional shortening. These metrics are often insensitive for detecting early or regional myocardial dysfunction. Strain echocardiography is a contemporary echocardiographic modality that may be more sensitive to perturbations in cardiac function. This investigation hypothesizes that strain echocardiography metrics correlate with severity of illness in pediatric sepsis despite normal fractional shortening.Single-center retrospective observational study.Tertiary 36-bed medical/surgical PICU.Pediatric patients admitted with sepsis.None.Twenty-three children with sepsis received an echocardiogram in the study period. Patients with sepsis demonstrated abnormal peak systolic longitudinal strain for age (mean = -0.13 ± 0.07; p < 0.01) and low normal peak systolic circumferential strain (mean = -0.17 ± 0.14; p = 0.02) compared with internal controls as well as previously published normal values. Depressed strain was demonstrated in the septic patients despite having normal fractional shortening (mean = 0.41; 95% CI, 0.38-0.43). On initial echocardiographic imaging, worsening peak systolic longitudinal strain was associated with increasing lactate (p = 0.04).Pediatric patients with sepsis demonstrate evidence of depressed strain echocardiography parameters not shown by fractional shortening that correlate with clinical indices of sepsis severity. Whether strain echocardiography could eventually assist in grading pediatric sepsis severity and affect management is an area for potential future investigation.

    View details for DOI 10.1097/PCC.0000000000000683

    View details for Web of Science ID 000379595900008

    View details for PubMedID 26963758

    View details for PubMedCentralID PMC4856561

  • Oropharyngeal dermoid cyst in an infant with intermittent airway obstruction. A case report. The neuroradiology journal Wagner, M. W., Haileselassie, B., Kannan, S., Chen, C., Poretti, A., Tunkel, D. E., Huisman, T. A. 2014; 27 (5): 627-631


    Dermoid cysts are benign epithelial inclusions and cystic lesions that may occur in several locations including the oropharynx. We describe the case of a two-month-old baby girl who presented with progressive respiratory distress, hypoxemia, and feeding difficulties because of an oropharyngeal dermoid cyst. The child had an airway work-up that included laryngoscopy. However, the mass remained undetected. This is most likely explained by the mobile nature of the lesion, prolapsing into the high nasopharynx in supine position. In our patient, magnetic resonance imaging (MRI), initially performed to rule out brainstem pathology, revealed an oropharyngeal dermoid cyst. This case shows the potential role of neuroimaging in the diagnostic work-up of a young child presenting with respiratory distress by excluding a central nervous system lesion and diagnosing an "unexpected" nasopharyngeal mass lesion. In addition, MRI allowed exclusion of skull base lesions of neural origin such as an anterior meningoencephalocele or heterotopic neuroglial tissue which would be managed differently from pharyngeal masses.

    View details for DOI 10.15274/NRJ-2014-10085

    View details for PubMedID 25260210

    View details for PubMedCentralID PMC4237111

  • Fat Embolism: Evolution of Histopathological Changes in the Rat Lung JOURNAL OF ORTHOPAEDIC RESEARCH McIff, T. E., Poisner, A. M., Herndon, B., Lankachandra, K., Schutt, S., HaileSelassie, B., Patel, S., Quinn, T., Adler, F., Molteni, A. 2010; 28 (2): 191-197


    The pathophysiology of Fat Embolism Syndrome (FES) is poorly understood and subject to some controversy. Evaluation of the evolution of histological changes in the lungs of patients with FES is impractical. The current theories of FES were established through acute clinical observations and acute animal experiments, but sequential changes in the histology of lungs over a prolonged period have not been made. The progressive effects of fat embolization of the lungs were examined in a rat model over a period of 11 days. Triolein, a major bone marrow fat, was administered to conscious Sprague-Dawley rats via the caudal vein. Rats were euthanized at 24, 48, 96 h, and 11 days, but some died within a few hours. Histomorphometric evaluations of lung tissue were made, including stains for fat, collagen, and smooth muscle actin. Arterial and arteriolar patency decreased progressively up to 96 h, but returned toward normal after 11 days. A striking finding was the very early presence of inflammation and fibrosis after only several hours, persisting up to 11 days. The results of this study provide evidence of both very early and prolonged changes due to fat embolization.

    View details for DOI 10.1002/jor.20963

    View details for Web of Science ID 000273675700008

    View details for PubMedID 19688870

  • Left Atrial Strain Predicts Adverse Outcomes in Hypertrophic Cardiomyopathy Circulation, American Heart Association's 2018 Scientific Sessions Vasquez, ., Ostrander, B., Lu, D., Ventoulis, I., Haileselassie, B., Goyal, S., Vakrou, S., Abraham, T. P., Abraham, R. M. 2018: A17186
  • ROLE OF DRP1/FIS1-MEDIATED MITOCHONDRIAL FRAGMENTATION IN SEPSIS-INDUCED MYOCARDIAL DYSFUNCTION Society of Critical Care Medicine Congress Haileselassie, B., Joshi, A., Mukherjee, R., Napier, B., Massis, L., Ostberg, N., Monack, D., Bernstein, D., Mochly-Rosen, D. 2019: 21