Introduction: Excess lipolysis and dysregulated fatty acid oxidation can exacerbate neuroglial injury and impair neurodevelopment. Neurodevelopment is also regulated by histone deacetylation and methylation, which often repress gene transcription and can alter cerebral metabolism. It is unknown if fatty acid metabolism and histone modifications are altered in the neonatal brain following cardiopulmonary bypass (CPB). Research Question: This study sought to determine if histone modifications regulating chromatin accessibility and gene transcription are altered in the brain or associated with changes in cerebral metabolism at 12-24hrs post-CPB. Methods: Fifteen neonatal swine underwent 3hrs of CPB prior to decannulation and survival for 12hrs, 18hrs, or 24hrs (N=5 per cohort). Three additional piglets underwent similar sham procedures with 4hr survival. Cortical brain tissue was then analyzed with liquid chromatography-mass spectrometry using an untargeted approach to quantify 129 metabolites and 45 histone modifications in each sample. Histone modifications with a statistically significant fold-change (FC) post-CPB ( P <0.0001) were correlated with metabolites across all timepoints of analysis. Results: In total, 6/45 (13%) histone modifications were significantly altered in cortical brain tissue following CPB. The acetylation of histone H4 on lysine residue 16 (H4K16ac) was reduced at 12-24hrs post-CPB (FC=0.7-0.8, P <0.0001 ), while trimethylation was enriched on histone H4 at lysine residue 20 (H4K20me3: FC=1.5-2.4; Figure ). H4K20me3 enrichment directly correlated with intermediates of fatty acid metabolism, specifically polyunsaturated long-chain acylcarnitines ( Table ). Histone H3 variants had enriched mono-methylation on lysine 36 residues at 12hrs (H33K36me1: FC=6.9, P <0.0001 ) and 18hrs post-CPB (H31K36me1: FC=1.6, P <0.0001 ). Histone H3 mono-methylation was also enriched on lysine residue 23 (H3K23me1) at 18hrs post-CPB (FC=5.1, P <0.0001 ), and phosphorylation on serine residue 10 (H3S10ph) was enriched at 24hrs post-CPB (FC=6.2, P <0.0001 ). Conclusion: Dynamic changes in histone methylation and deacetylation post-CPB may impact metabolic homeostasis in the neonatal brain during critical periods of neurodevelopment. Further investigations are warranted to elucidate how alterations in lipolysis, fatty acid oxidation, chromatin accessibility, and gene transcription may affect myelination, neuroglial injury, and neurodevelopment in neonates requiring cardiac surgery.

Introduction: We present a novel demonstration of brain-directed management of venoarterial extracorporeal membrane oxygenation (ECMO) using real-time feedback from non-invasive neurometabolic optical monitoring (NOM) of the cerebral oxygen extraction fraction (OEF) in pediatric swine. In our prior work, OEF>0.82 was associated with hypoxic-ischemic brain injury during ECMO. Maintaining OEF below this threshold may prevent injury. Hypothesis: Cerebral OEF levels of 0.8, 0.7, and 0.6 will be achieved during 7 h of brain-directed ECMO after prolonged cardiac arrest. Methods: Continuous cerebral OEF was acquired in a pediatric swine model ( sus scrofa , 8-12 kg) of ECMO-assisted cardiopulmonary resuscitation (CPR) using NOM on the left forehead. Animals had 8 min of ventricular fibrillation followed by 30 min of low-flow ECMO (20 ml/kg/min) with epinephrine (0.02 mg/kg) boluses every 4 min to simulate prolonged CPR. Then, ECMO flow rate was increased to 70-100 ml/kg/min to reflect clinical return of circulation. After 1 h, animals were randomized to a cerebral OEF target of 0.8 (n=11), 0.7 (n=12), or 0.6 (n=12) and brain-directed ECMO management was performed for 7 h; OEF was re-assessed every 5 min. If the OEF target was not achieved (±0.05 of target), first, ECMO flow rate was adjusted between 50-120 ml/kg/min, second, arterial blood pressure (ABP) was modulated using vasoactive infusions. Blood gas, hematocrit, anticoagulation, and anesthesia were otherwise standardized across all subjects. Mitochondrial respirometry assessed maximal oxidative phosphorylation of cortical tissue following ECMO as a metric of brain health which we have shown to correlate with neurologic outcomes across injury models. Associations with mean cerebral OEF, ECMO pump flow, and ABP were examined by linear regression. Results: Brain-directed ECMO achieved and maintained respective OEF targets for 79% [57, 93] of the 7 h period (median [IQR] across animals). 71% (n=25/35) of animals achieved their target within 1 h of initiating brain-directed management. OEF, but not pump flow or ABP, was significantly correlated with maximal oxidative phosphorylation (p=0.005). Conclusion: Our results demonstrate the efficacy and precision of real-time modulation of cerebral OEF during ECMO based on neurophysiologic feedback from the individual patient. The association of OEF with brain health suggests that brain-directed management may provide new opportunities to mitigate neurological injury.

Neonates undergoing cardiac surgery involving aortic arch reconstruction are at an increased risk for hypoxic-ischemic brain injury. Deep hypothermia is utilized to help mitigate this risk when periods of circulatory arrest are needed for surgical repair. Here, we investigate correlations between non-invasive optical neuromonitoring of cerebral hemodynamics, which has recently shown promise for the prediction of postoperative white matter injury in this patient population, and invasive cerebral microdialysis biomarkers. We compared cerebral tissue oxygen saturation (StO2), relative total hemoglobin concentration (rTHC), and relative cerebral blood flow (rCBF) measured by optics against the microdialysis biomarkers of metabolic stress and injury (lactate–pyruvate ratio (LPR) and glycerol) in neonatal swine models of deep hypothermic cardiopulmonary bypass (DHCPB), selective antegrade cerebral perfusion (SACP), and deep hypothermic circulatory arrest (DHCA). All three optical parameters were negatively correlated with LPR and glycerol in DHCA animals. Elevation of LPR was found to precede the elevation of glycerol by 30–60 min. From these data, thresholds for the detection of hypoxic-ischemia-associated cerebral metabolic distress and neurological injury are suggested. In total, this work provides insight into the timing and mechanisms of neurological injury following hypoxic-ischemia and reports a quantitative relationship between hypoxic-ischemia severity and neurological injury that may inform DHCA management.

Purpose The purpose of this study is to evaluate the impact in the development of intracerebral hemorrhage in elderly critically ill patients who received prophylactic subcutaneous unfractionated heparin (SCUFH) less than 24 hours after undergoing emergency neurosurgery. Methods A retrospective analysis was performed on patients who underwent emergency neurosurgery and were admitted to the surgical intensive care unit (SICU) at a tertiary care center over a 10-year period. Administration of prophylactic SCUFH within 24 hours of neurosurgery was required for inclusion. Demographic and clinical characteristics were recorded. The primary outcome was a rate of postoperative hemorrhagic complications with respect to age. Results We identified 223 emergency neurosurgical patients: 100 (45%) patients did not receive prophylactic SCUFH and were excluded. The remaining 123 (55%) patients met all inclusion criteria, of whom 73 (59%) patients were under 65 years old, and 50 (41%) patients were over 65 years old. Patients under 65 years old had significantly lower body mass index (BMI), lower Acute Physiology and Chronic Health Evaluation (APACHE) II, APACHE III, and Simplified Acute Physiology Score (SAPS) scores, and shorter median SICU length of stay compared to patients over 65 years old. No statistically significant difference in the rate of postoperative hemorrhagic or non-hemorrhagic neurological complications was observed between patients in either age group. Conclusion Age over 65 years was not associated with a higher risk of postoperative hemorrhage in patients who received SCUFH after emergency neurosurgery. SCUFH can be safely used as a chemoprophylactic agent against venous thromboembolism for elderly patients when used within 24 hours after emergency neurosurgery.

Tambo, Willians1; Lee, Andrew2; Sisa, Ivan1; Diaz, Erick3; Aronowitz, Danielle2; Torres, Fernando1; Barrera, Rafael2 Author Information

Grunauer, Michelle1; Mikesell, Caley2; Bustamante, Gabriela2; Zambrano, Kevin2; Icaza-Freire, Andrea2; Aronowitz, Danielle3; Danilo Gavilanes, Antonio W.4; Barrera, Rafael5 Author Information

BACKGROUND:Healthcare professionals in the intensive care unit (ICU) confront stressful working conditions. Morning rounds involve several hours of prolonged standing and uninterrupted concentration each day and require both mental and physical endurance from the entire care team. There is concern that work-related fatigue among ICU practitioners will compromise their ability to safely and effectively care for their patients. To address this concern, the surgical intensive care unit (SICU) at Long Island Jewish Medical Center implemented an initiative to promote provider wellness through "active breaks" during rounds.MATERIALS AND METHODS:Between October and December 2019, 30 physicians, physician assistants, nurses, and students collectively engaged in active breaks during SICU rounds and then completed a 7-question, post-test survey to assess their experience. The survey consisted of both closed-end and open-ended questions. The data were then analyzed using simple statistics.RESULTS:In response to closed-ended questioning, the majority of participants agreed that active breaks relieved stress (27/30; 90%), promoted wellness (29/30; 96.7%), and improved team morale (29/30; 93.1%). When given the options of tricep dips, squats or push-ups, squats were the favored activity during breaks (17/30; 56.7%). Most of the participants (27/30; 90%) considered the active breaks to be appropriate for the working environment; two participants had no opinion on this matter. Approximately 90% of the respondents were interested in maintaining active breaks as part of the routine of morning rounds.CONCLUSIONS:Our assessment suggests active breaks during rounds are a healthy outlet to address the inherent stress associated with critical care. This initiative also potentially protects healthcare providers from burnout and, consequentially, improves the quality of patient care.

Pediatric Intensive Care Units (PICUs) provide multidisciplinary care to critically ill children and their families. Grief is present throughout the trajectory of illness and can peak around the time of death or non-death losses. The objective of this study was to assess how PICUs around the world implement grief and bereavement care (GBC) as part of an integrated model of care. This is a multicenter cross-sectional, prospective survey study. Questionnaires with multiple-choice and open-ended questions focusing on unit infrastructure, personnel, policies, limited patient data, and practices related to GBC for families and health care professionals (HCPs) were completed by on-site researchers, who were HCPs on the direct care of patients. PICU fulfillment of GBC goals was evaluated using a custom scoring based on indicators developed by the Initiative for Pediatric Palliative Care (IPPC). We compared average total and individual items fulfillment scores according to the respective country's World Bank income. Patient characteristics and details of unit infrastructure were also evaluated as potential predictors of total GBC fulfillment scores. Statistical analysis included multilevel generalized linear models (GLM) with a Gaussian distribution adjusted by child age/gender and clustering by center, using high income countries (HICs) as the comparative reference. Additionally, we applied principals of content analysis to analyze and summarize open-ended answers to contextualize qualitative data. The study included 34 PICUs from 18 countries: high-income countries (HICs): 32.4%, upper middle-income countries (UMICs): 44.1%, low middle-income and low-income countries (LMI/LICs): 23.5%. All groups reported some compliance with GBC goals; no group reported perfect fulfillment. We found statistically significant differences in GBC fulfillment scores between HICs and UMICs (specifically, HCP grief support), and between HICs and LMICs (specifically, family grief support and HCP grief support). PICUs world-wide provide some GBC, independent of income, but barriers include lack of financial support, time, and training, overall unit culture, presence of a palliative care consultation service, and varying cultural perceptions of child death. Disparities in GBC for families and HCPs exist and were related to the native countries' income level. Identifying barriers to support families and HCPs, can lead to opportunities of improving GBC in PICUs world-wide.

Faliks, Bradley; Aronowitz, Danielle; Abramov, Rachel; Smith, Candace; Patel, Vihas; Nicastro, Jeffrey; Barrera, Rafael Author Information

Countless medical mission trips have traveled across the globe to provide health care, medical education, and social services to underserved populations in need. However, establishing sustainable health care initiatives in these remote locations has been challenging. Here we describe the successful strategies use by volunteers from the Medical Missions for Children (MMFC) and the Global Health Initiate of the Surgical Service Line of Northwell Health in our mission trips to Quito, Ecuador.

Aronowitz, Danielle; Sfakianos, Maria; Platz, John; Bank, Matthew; Kalyon, Bilge; Shah, Ujas; Lee, Andrew; Nealon, William; Athanasatos, George; Gandras, Eric; Ohngemach, Daniel Author Information

Background: According to the Surviving Sepsis Campaign (SSC) guidelines, norepinephrine is the preferred vasopressor over phenylephrine when treating hemodynamically unstable septic patients. However, few studies have directly compared the use of these 2 vasopressors in septic shock patients. Objective: To compare 28-day mortality and surgical intensive care unit (SICU) length of stay in septic shock patients treated with phenylephrine and norepinephrine. Methods: Retrospective chart review of septic shock patients admitted from January 2012 through June 2017, who were treated with either phenylephrine or norepinephrine. The primary endpoint was assessment of 28-day mortality, secondary endpoint was SICU length of stay. The same endpoints were also evaluated specifically in patients with known cardiac disease. Results: Of the 30 patients included, 15 had been treated with norepinephrine and 15 with phenylephrine. Patients in either group had similar demographics and SOFA scores. No statistically significant difference was observed in either 28-day mortality (P=0.200) or SICU length of stay (P=0.544) between the 2 vasopressor groups. There was still no significant difference in the primary or secondary endpoints when compared among patients with baseline cardiac disease. Conclusion: Phenylephrine use in patients with septic shock does not appear to increase risk of 28-day mortality or prolong SICU length of stay when compared with using norepinephrine. However, its use also does not improve outcomes, even in patients with significant cardiac history.

Aronowitz, Danielle; Riggins, Tunisa; Cavaciuti, Mary; Lagasca, Angeli; Jose, Robert; Mootoo, Stephen; Barrera, Rafael Author Information

Aims/hypothesis Adult beta cells in the pancreas are the sole source of insulin in the body. Beta cell loss or increased demand for insulin impose metabolic challenges because adult beta cells are generally quiescent and infrequently re-enter the cell division cycle. The aim of this study is to test the hypothesis that a family of proto-oncogene microRNAs that includes miR-17-92 and miR-106b-25 clusters regulates beta cell proliferation or function in the adult endocrine pancreas. Methods To elucidate the role of miR-17-92 and miR-106b-25 clusters in beta cells, we used a conditional miR-17-92/miR-106b-25 knockout mouse model. We employed metabolic assays in vivo and ex vivo, together with advanced microscopy of pancreatic sections, bioinformatics, mass spectrometry and next generation sequencing, to examine potential targets of miR-17-92/miR-106b-25, by which they might regulate beta cell proliferation and function. Results We demonstrate that miR-17-92/miR-106b-25 regulate the adult beta cell mitotic checkpoint and that miR-17-92/miR-106b-25 deficiency results in reduction in beta cell mass in vivo. Furthermore, we reveal a critical role for miR-17-92/miR-106b-25 in glucose homeostasis and in controlling insulin secretion. We identify protein kinase A as a new relevant molecular pathway downstream of miR-17-92/miR-106b-25 in control of adult beta cell division and glucose homeostasis. Conclusions/interpretation The study contributes to the understanding of proto-oncogene miRNAs in the normal, untransformed endocrine pancreas and illustrates new genetic means for regulation of beta cell mitosis and function by non-coding RNAs. Data availability Sequencing data that support the findings of this study have been deposited in GEO with the accession code GSE126516.

Aronowitz, Danielle1; Sikachi, Rutuja1; Wu, Wenchen2; Smith, Candace2; Barrera, Rafael3 Author Information

Critical Care Medicine • Volume 46 • Number 1 (Supplement) www.ccmjournal.org Learning Objectives: Intensive care units rely on accurate exchange of knowledge and efficient task delegation to improve outcomes and avoid complications. Within healthcare education, exposure to team-based practice is essential for training future healthcare providers. A pilot educational program for healthcare students using an inter-professional (IP) approach was conducted in a surgical intensive care unit (SICU). The objectives of this activity were to assess communication skills, delineate roles, exchange knowledge, and develop teamwork among students during an experiential rotation. Methods: Medical (M), physician assistant (PA) and pharmacy (Ph) students were teamed during experiential rotations in a SICU to develop a comprehensive patient care plan (CPCP). Each team presented their CPCP on morning rounds. A post-activity survey assessed students’ self-reported changes in knowledge and expertise based on their IP experience. Six statements were listed and accompanied with a 5-point Likert scale. Students reflected on their experience qualitatively and evaluated their communication skills. The data were analyzed using a mixed methods approach. Results: A total of 32 students (8 M, 8 PA, 16 Ph) participated in the program. 31/32 (97%) students agreed that the activity increased their communication skills, understanding of their roles, and their knowledge. All students agreed that this exercise increased their clinical application skills, and ability to work on a healthcare team. 26/32 (81%) students improved their ability to create a comprehensive healthcare plan. Qualitative responses emphasized student interest in more IP interactions and a need for communication skills enrichment among Ph students. Conclusions: This IP model can teach and promote effective teamwork, enhance knowledge and improve communication among future healthcare providers. The majority of students from 3 healthcare professions attested to the efficacy of this strategy. The discrepancy in communication skills among Ph students is likely multifactorial and could benefit from more frequent IP skills training similar to this pilot exercise.

Purpose: The purpose of this study is to review published reports and contribute new cases of umbilical cord ulceration (UCU) with perinatal hemorrhage into the amniotic cavity in the setting of duodenal or jejuna! obstruction because knowledge of this sequence is poorly disseminated and could be lifesaving. Methods: Published reports of UCU with hemorrhage associated with congenital duodenal or jejunal obstruction were reviewed. Chart review was conducted for the cases encountered at our institutions between January 2008 and March 2017. We noted perinatal complications, method of delivery, gestational age, birth weight, gender, number, location, and pathologic description of umbilical cord ulcers, and outcome. Results: Thirty-one reports and 7 new cases were studied. Perinatal complications included: preterm labor or preterm premature rupture of membranes: 63%; fetal distress: 95%; mean gestational age: 33 weeks; premature gestation: 95%; bloody amniotic fluid: 90%. Pathological analysis of UCUs revealed solitary, multifocal, helical and punched-out lesions. There were 12 neonatal deaths (32%), and 12 intrauterine deaths (32%). Survival rate was 37%. Conclusions: UCU with perinatal hemorrhage is associated with duodenal and jejuna! obstruction. Knowing the typical clinical signs of this potential catastrophic complication could prompt lifesaving delivery. Type of study: Prognostic (C) 2017 Elsevier Inc. All rights reserved.