Publications by authors named "Patrick M Kochanek"

444 Publications

Association Between Hyperoxemia and Increased Cell-Free Plasma Hemoglobin During Cardiopulmonary Bypass in Infants and Children.

Pediatr Crit Care Med 2021 Sep 24. Epub 2021 Sep 24.

Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA. Department of Pediatrics, Division of Critical Care Medicine, Ochsner Hospital for Children, New Orleans, LA. Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA. UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA. Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA.

Objectives: To determine potential risk factors for severe hemolysis during pediatric cardiopulmonary bypass and examine whether supraphysiologic levels of oxygen and cardiopulmonary bypass duration are associated with hemolysis.

Design: Prospective observational study.

Setting: Cardiac ICU in a university-affiliated children's hospital.

Patients: Greater than 1 month to less than 18 years old patients undergoing cardiopulmonary bypass for cardiac surgery.

Interventions: None.

Measurements And Main Results: Plasma samples from 100 patients to assess cell-free plasma hemoglobin levels were obtained at start cardiopulmonary bypass, at the end of cardiopulmonary bypass, and 2 and 24 hours after reperfusion. Arterial blood gas samples were obtained before and every 30 minutes during cardiopulmonary bypass. Patient demographics and laboratory data were collected from the electronic medical record. Plasma hemoglobin levels peaked at the end of cardiopulmonary bypass and haptoglobin levels continued to fall throughout all time points. There were 44 patients with severe hemolysis (change in cell-free plasma hemoglobin > 50 mg/dL). Younger age (odds ratio/SD 0.45 [95% CI, 0.25-0.81]) and higher mean PaO2 × cardiopulmonary bypass duration (31.11 [1.46-664.64]) were identified as risk factors for severe hemolysis in multivariable analysis. Severe hemolysis was associated with longer hospital and ICU lengths of stay as well as acute kidney injury.

Conclusions: We observed younger age and the exposure to both oxygen and duration of cardiopulmonary bypass as risk factors for hemolysis. Oxygen delivery through the cardiopulmonary bypass circuit is an easily modifiable risk factor. Its role in the production of reactive oxygen species that could alter the erythrocyte membrane deserves further examination in larger prospective studies.
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http://dx.doi.org/10.1097/PCC.0000000000002814DOI Listing
September 2021

Genetic Variants Associated With Intraparenchymal Hemorrhage Progression After Traumatic Brain Injury.

JAMA Netw Open 2021 Jul 1;4(7):e2116839. Epub 2021 Jul 1.

Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Importance: Intracerebral hemorrhage progression is associated with unfavorable outcome after traumatic brain injury (TBI). No effective treatments are currently available. This secondary injury process reflects an extreme form of vasogenic edema and blood-brain barrier breakdown. The sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) cation channel is a key underlying mechanism. A phase 2 trial of SUR1-TRPM4 inhibition in contusional TBI is ongoing, and a phase 3 trial is being designed. Targeted identification of patients at increased risk for hemorrhage progression may inform prognostication, trial design (including patient selection), and ultimately treatment response.

Objective: To determine whether ABCC8 (SUR1) and TRPM4 genetic variability are associated with intraparenchymal hemorrhage (IPH) progression after severe TBI, based on the putative involvement of the SUR1-TRPM4 channel in this pathophysiology.

Design, Setting, And Participants: In this genetic association study, DNA was extracted from 416 patients with severe TBI prospectively enrolled from a level I trauma academic medical center from May 9, 2002, to August 8, 2014. Forty ABCC8 and TRPM4 single-nucleotide variants (SNVs) were genotyped (multiplex, unbiased). Data were analyzed from January 7, 2020, to May 3, 2021.

Main Outcomes And Measures: Primary analyses addressed IPH progression at 6, 24, and 120 hours in patients without acute craniectomy (n = 321). Multivariable regressions and receiver operating characteristic curves assessed SNV and haplotype associations with progression. Spatial modeling and functional predictions were determined using standard software.

Results: Of the 321 patients included in the analysis (mean [SD] age, 37.0 [16.3] years; 247 [76.9%] male), IPH progression occurred in 102. Four ABCC8 SNVs were associated with markedly increased odds of progression (rs2237982 [odds ratio (OR), 2.60-3.80; 95% CI, 1.14-5.90 to 1.80-8.02; P = .02 to P < .001], rs2283261 [OR, 3.37-4.77; 95% CI, 1.07-10.77 to 1.89-12.07; P = .04 to P = .001], rs3819521 [OR, 2.96-3.92; 95% CI, 1.13-7.75 to 1.42-10.87; P = .03 to P = .009], and rs8192695 [OR, 3.06-4.95; 95% CI, 1.02-9.12 to 1.67-14.68]; P = .03-.004). These are brain-specific expression quantitative trait loci (eQTL) associated with increased ABCC8 messenger RNA levels. Regulatory annotations revealed promoter and enhancer marks and strong and/or active brain-tissue transcription, directionally consistent with increased progression. Three SNVs (rs2283261, rs2237982, and rs3819521) in this cohort have been associated with intracranial hypertension. Four TRPM4 SNVs were associated with decreased IPH progression (rs3760666 [OR, 0.40-0.49; 95% CI, 0.19-0.86 to 0.27-0.89; P = .02 to P = .009], rs1477363 [OR, 0.40-0.43; 95% CI, 0.18-0.88 to 0.23-0.81; P = .02 to P = .006], rs10410857 [OR, 0.36-0.41; 95% CI, 0.20-0.67 to 0.20-0.85; P = .02 to P = .001], and rs909010 [OR, 0.27-0.40; 95% CI, 0.12-0.62 to 0.16-0.58; P = .002 to P < .001]). Significant SNVs in both genes cluster downstream, flanking exons encoding the receptor site and SUR1-TRPM4 binding interface. Adding genetic variation to clinical models improved receiver operating characteristic curve performance from 0.6959 to 0.8030 (P = .003).

Conclusions And Relevance: In this genetic association study, 8 ABCC8 and TRPM4 SNVs were associated with IPH progression. Spatial clustering, brain-specific eQTL, and regulatory annotations suggest biological plausibility. These findings may have important implications for neurocritical care risk stratification, patient selection, and precision medicine, including an upcoming phase 3 trial design for SUR1-TRPM4 inhibition in severe TBI.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.16839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314141PMC
July 2021

Fluid therapy after brain injury: the pendulum swings again.

Lancet Neurol 2021 08;20(8):587-589

Barrow Neurological Institute, Phoenix, AZ, USA.

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http://dx.doi.org/10.1016/S1474-4422(21)00204-0DOI Listing
August 2021

An exploratory assessment of serum biomarkers of post-cardiac arrest syndrome in children.

Resuscitation 2021 Oct 14;167:307-316. Epub 2021 Jul 14.

Critical Care Medicine UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, United States; Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Children's Neuroscience Institute, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address:

Aim: We hypothesized that serum biomarkers of inflammation including chemokine, cytokine, pituitary hormones, and growth factors following cardiac arrest in children would independently associate with 6-month neurologic outcome.

Methods: In this prospective observational single center study of children with in-hospital and out-of-hospital cardiac arrest surviving to intensive care unit admission, serum was obtained twice per 24 h period between 0 h and 96 h and once at approximately 196 h post-cardiac arrest. Inflammatory mediators, hormones, and growth factors were analyzed by Luminex Multiplex Bead Immunoassay. We recorded demographics, resuscitation characteristics, and Pediatric Cerebral Performance Category (PCPC) at 6 months. We analyzed the association and area under the curve (AUC) of biomarker levels with favorable (PCPC 1-3) or unfavorable (PCPC 4-6, or >1 increase from baseline) outcome.

Results: Forty-two children (50% female; median age of 2.5 [IQR: 0.4-10.2]) were enrolled and 18 (42%) died prior to 6-month follow up. Receiver operator curves for initial levels of ciliary neurotrophic factor (CNTF, AUC 0.84, 95% CI 0.73-0.96, p < 0.001) and interleukin (IL-17, AUC 0.84, 95% CI 0.73-0.97, p < 0.001) best classified favorable versus unfavorable 6-month outcome. In multivariable analysis, initial levels of CNTF and IL-17 remained associated with 6-month PCPC. Peak levels of interferon-γ-inducible protein 10 (IP-10), CNTF, and hepatocyte growth factor (HGF) were also independently associated with outcome.

Conclusion: Increased serum concentrations of CNTF and IL-17 associated with unfavorable 6-month neurologic outcome of children surviving cardiac arrest. Further investigation of the prognostic utility and roles of CNTF and IL-17 in the pathophysiology of post-cardiac arrest syndrome are warranted. This project is registered with clinicaltrials.gov (NCT00797680) as "Duration of Hypothermia for Neuroprotection after Pediatric Cardiac Arrest: A Randomized, Controlled Trial".
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http://dx.doi.org/10.1016/j.resuscitation.2021.07.007DOI Listing
October 2021

Choice of Whole Blood versus Lactated Ringer's Resuscitation Modifies the Relationship between Blood Pressure Target and Functional Outcome after Traumatic Brain Injury plus Hemorrhagic Shock in Mice.

J Neurotrauma 2021 Oct 15;38(20):2907-2917. Epub 2021 Sep 15.

Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Civilian traumatic brain injury (TBI) guidelines recommend resuscitation of patients with hypotensive TBI with crystalloids. Increasing evidence, however, suggests that whole blood (WB) resuscitation may improve physiological and survival outcomes at lower resuscitation volumes, and potentially at a lower mean arterial blood pressure (MAP), than crystalloid after TBI and hemorrhagic shock (HS). The objective of this study was to assess whether WB resuscitation with two different MAP targets improved behavioral and histological outcomes compared with lactated Ringer's (LR) in a mouse model of TBI+HS. Anesthetized mice ( = 40) underwent controlled cortical impact (CCI) followed by HS (MAP = 25-27 mm Hg; 25 min) and were randomized to five groups for a 90 min resuscitation: LR with MAP target of 70 mm Hg (LR), LR, WB, WB, and monitored sham. Mice received a 20 mL/kg bolus of LR or autologous WB followed by LR boluses (10 mL/kg) every 5 min for MAP below target. Shed blood was reinfused after 90 min. Morris Water Maze testing was performed on days 14-20 post-injury. Mice were euthanized (21 d) to assess contusion and total brain volumes. Latency to find the hidden platform was greater versus sham for LR ( < 0.002) and WB ( < 0.007) but not LR or WB. The WB resuscitation did not reduce contusion volume or brain tissue loss. The WB targeting a MAP of 60 mm Hg did not compromise function versus a 70 mm Hg target after CCI+HS, but further reduced fluid requirements ( 0.03). Using LR, higher achieved MAP was associated with better behavioral performance (rho = -0.67,  0.028). Use of WB may allow lower MAP targets without compromising functional outcome, which could facilitate pre-hospital TBI resuscitation.
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http://dx.doi.org/10.1089/neu.2021.0157DOI Listing
October 2021

Cardiopulmonary Resuscitation and Rescue Therapies.

Crit Care Med 2021 09;49(9):1375-1388

Department of Surgery, University of Michigan, Ann Arbor, MI.

The history of cardiopulmonary resuscitation and the Society of Critical Care Medicine have much in common, as many of the founders of the Society of Critical Care Medicine focused on understanding and improving outcomes from cardiac arrest. We review the history, the current, and future state of cardiopulmonary resuscitation.
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http://dx.doi.org/10.1097/CCM.0000000000005106DOI Listing
September 2021

Roadmap for Advancing Pre-Clinical Science in Traumatic Brain Injury.

J Neurotrauma 2021 Aug 13. Epub 2021 Aug 13.

The Roskamp Institute, Sarasota, Florida, USA.

Pre-clinical models of disease have long played important roles in the advancement of new treatments. However, in traumatic brain injury (TBI), despite the availability of numerous model systems, translation from bench to bedside remains elusive. Integrating clinical relevance into pre-clinical model development is a critical step toward advancing therapies for TBI patients across the spectrum of injury severity. Pre-clinical models include and animal work-both small and large-and modeling. The wide range of pre-clinical models reflect substantial attempts to replicate multiple aspects of TBI sequelae in humans. Although these models reveal multiple putative mechanisms underlying TBI pathophysiology, failures to translate these findings into successful clinical trials call into question the clinical relevance and applicability of the models. Here, we address the promises and pitfalls of pre-clinical models with the goal of evolving frameworks that will advance translational TBI research across models, injury types, and the heterogenous etiology of pathology.
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http://dx.doi.org/10.1089/neu.2021.0094DOI Listing
August 2021

Targeting "Natural Born Killers" to Modulate Immune Suppression in Neurocritical Care.

Neurocrit Care 2021 Jun 1. Epub 2021 Jun 1.

Department of Critical Care Medicine, Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, John G. Rangos Research Center, 6th Floor 4401 Penn Avenue, Pittsburgh, PA, USA.

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http://dx.doi.org/10.1007/s12028-021-01235-yDOI Listing
June 2021

Neurological Complications Acquired During Pediatric Critical Illness: Exploratory "Mixed Graphical Modeling" Analysis Using Serum Biomarker Levels.

Pediatr Crit Care Med 2021 10;22(10):906-914

Department of Computer Science, University of Pittsburgh, Pittsburgh, PA.

Objectives: Neurologic complications, consisting of the acute development of a neurologic disorder, that is, not present at admission but develops during the course of illness, can be difficult to detect in the PICU due to sedation, neuromuscular blockade, and young age. We evaluated the direct relationships of serum biomarkers and clinical variables to the development of neurologic complications. Analysis was performed using mixed graphical models, a machine learning approach that allows inference of cause-effect associations from continuous and discrete data.

Design: Secondary analysis of a previous prospective observational study.

Setting: PICU, single quaternary-care center.

Patients: Individuals admitted to the PICU, younger than18 years old, with intravascular access via an indwelling catheter.

Interventions: None.

Measurements: About 101 patients were included in this analysis. Serum (days 1-7) was analyzed for glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, and alpha-II spectrin breakdown product 150 utilizing enzyme-linked immunosorbent assays. Serum levels of neuron-specific enolase, myelin basic protein, and S100 calcium binding protein B used in these models were reported previously. Demographic data, use of selected clinical therapies, lengths of stay, and ancillary neurologic testing (head CT, brain MRI, and electroencephalogram) results were recorded. The Mixed Graphical Model-Fast-Causal Inference-Maximum algorithm was applied to the dataset.

Main Results: About 13 of 101 patients developed a neurologic complication during their critical illness. The mixed graphical model identified peak levels of the neuronal biomarker neuron-specific enolase and ubiquitin C-terminal hydrolase-L1, and the astrocyte biomarker glial fibrillary acidic protein to be the direct causal determinants for the development of a neurologic complication; in contrast, clinical variables including age, sex, length of stay, and primary neurologic diagnosis were not direct causal determinants.

Conclusions: Graphical models that include biomarkers in addition to clinical data are promising methods to evaluate direct relationships in the development of neurologic complications in critically ill children. Future work is required to validate and refine these models further, to determine if they can be used to predict which patients are at risk for/or with early neurologic complications.
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http://dx.doi.org/10.1097/PCC.0000000000002776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490289PMC
October 2021

Clinical Deterioration and Neurocritical Care Utilization in Pediatric Patients With Glasgow Coma Scale Score of 9-13 After Traumatic Brain Injury: Associations With Patient and Injury Characteristics.

Pediatr Crit Care Med 2021 May 12. Epub 2021 May 12.

1 Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA. 2 Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA. 3 Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA. 4 Brain Care Institute, Children's Hospital of Pittsburgh, Pittsburgh, PA. 5 Department of Pediatrics, Division of Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN. 6 Department of Neurosurgery, University of Texas at Austin, Austin, TX. 7 Department of Surgery, University of Pittsburgh, Pittsburgh, PA. 8 Children's Neuroscience Institute, Pittsburgh, PA. 9 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA.

Objectives: To define the clinical characteristics of hospitalized children with moderate traumatic brain injury and identify factors associated with deterioration to severe traumatic brain injury.

Design: Retrospective cohort study.

Setting: Tertiary Children's Hospital with Level 1 Trauma Center designation.

Patients: Inpatient children less than 18 years old with an International Classification of Diseases code for traumatic brain injury and an admission Glasgow Coma Scale score of 9-13.

Measurements And Results: We queried the National Trauma Data Bank for our institutional data and identified 177 patients with moderate traumatic brain injury from 2010 to 2017. These patients were then linked to the electronic health record to obtain baseline and injury characteristics, laboratory data, serial Glasgow Coma Scale scores, CT findings, and neurocritical care interventions. Clinical deterioration was defined as greater than or equal to 2 recorded values of Glasgow Coma Scale scores less than or equal to 8 during the first 48 hours of hospitalization. Thirty-seven patients experienced deterioration. Children who deteriorated were more likely to require intubation (73% vs 26%), have generalized edema, subdural hematoma, or contusion on CT scan (30% vs 8%, 57% vs 37%, 35% vs 16%, respectively), receive hypertonic saline (38% vs 7%), undergo intracranial pressure monitoring (24% vs 0%), were more likely to be transferred to inpatient rehabilitation following hospital discharge (32% vs 5%), and incur greater costs of care ($25,568 vs $10,724) (all p < 0.01). There was no mortality in this cohort. Multivariable regression demonstrated that a higher Injury Severity Score, a higher initial international normalized ratio, and a lower admission Glasgow Coma Scale score were associated with deterioration to severe traumatic brain injury in the first 48 hours (p < 0.05 for all).

Conclusions: A substantial subset of children (21%) presenting with moderate traumatic brain injury at a Level 1 pediatric trauma center experienced deterioration in the first 48 hours, requiring additional resource utilization associated with increased cost of care. Deterioration was independently associated with an increased international normalized ratio higher Injury Severity Score, and a lower admission Glasgow Coma Scale score.
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http://dx.doi.org/10.1097/PCC.0000000000002767DOI Listing
May 2021

Sustained Dysbiosis and Decreased Fecal Short-Chain Fatty Acids after Traumatic Brain Injury and Impact on Neurologic Outcome.

J Neurotrauma 2021 Sep 7;38(18):2610-2621. Epub 2021 Jun 7.

Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Traumatic brain injury (TBI) alters microbial populations present in the gut, which may impact healing and tissue recovery. However, the duration and impact of these changes on outcome from TBI are unknown. Short-chain fatty acids (SCFAs), produced by bacterial fermentation of dietary fiber, are important signaling molecules in the microbiota gut-brain axis. We hypothesized that TBI would lead to a sustained reduction in SCFA producing bacteria, fecal SCFAs concentration, and administration of soluble SCFAs would improve functional outcome after TBI. Adult mice ( = 10) had the controlled cortical impact (CCI) model of TBI performed (6 m/sec, 2-mm depth, 50-msec dwell). Stool samples were collected serially until 28 days after CCI and analyzed for SCFA concentration by high-performance liquid chromatography-mass spectrometry/mass spectrometry and microbiome analyzed by 16S gene sequencing. In a separate experiment, mice ( = 10/group) were randomized 2 weeks before CCI to standard drinking water or water supplemented with the SCFAs acetate (67.5 mM), propionate (25.9 mM), and butyrate (40 mM). Morris water maze performance was assessed on post-injury Days 14-19. Alpha diversity remained stable until 72 h, at which point a decline in diversity was observed without recovery out to 28 days. The taxonomic composition of post-TBI fecal samples demonstrated depletion of bacteria from , , and families, and enrichment of bacteria from the family. Analysis from paired fecal samples revealed a reduction in total SCFAs at 24 h and 28 days after TBI. Acetate, the most abundant SCFA detected in the fecal samples, was reduced at 7 days and 28 days after TBI. SCFA administration improved spatial learning after TBI versus standard drinking water. In conclusion, TBI is associated with reduced richness and diversity of commensal microbiota in the gut and a reduction in SCFAs detected in stool. Supplementation of soluble SCFAs improves spatial learning after TBI.
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http://dx.doi.org/10.1089/neu.2020.7506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403202PMC
September 2021

CSF lipocalin-2 increases early in subarachnoid hemorrhage are associated with neuroinflammation and unfavorable outcome.

J Cereb Blood Flow Metab 2021 Oct 5;41(10):2524-2533. Epub 2021 May 5.

Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.

Lipocalin-2 mediates neuro-inflammation and iron homeostasis in vascular injuries of the central nervous system (CNS) and is upregulated in extra-CNS systemic inflammation. We postulate that cerebrospinal fluid (CSF) and blood lipocalin-2 levels are associated with markers of inflammation and functional outcome in subarachnoid hemorrhage (SAH). We prospectively enrolled 67 SAH subjects, serially measured CSF and plasma lipocalin-2, matrix metallopeptidase 9 (MMP-9), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) on post-SAH days 1-5 and assessed outcome by modified Rankin Scale (mRS) every 3 months. Unfavorable outcome is defined as mRS > 2. Twenty non-SAH patients undergoing lumbar drain trial were enrolled as controls. Lipocalin-2 was detectable in the CSF and significantly higher in SAH compared to controls (p < 0.0001). Higher CSF LCN2 throughout post-SAH days 1-5 was associated with unfavorable outcome at 3 (p = 0.0031) and 6 months (p = 0.014). Specifically, higher CSF lipocalin-2 on post-SAH days 3 (p = 0.036) and 5 (p = 0.016) were associated with unfavorable 3-month outcome. CSF lipocalin-2 levels positively correlated with CSF IL-6, TNF-α and MMP-9 levels. Higher plasma lipocalin-2 levels over time were associated with worse 6-month outcome. Additional studies are required to understand the role of lipocalin-2 in SAH and to validate CSF lipocalin-2 as a potential biomarker for SAH outcome.
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http://dx.doi.org/10.1177/0271678X211012110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504948PMC
October 2021

Smiling on the Bright Future of Pediatric Critical Care Medicine and the "Task(er)" at Hand.

Pediatr Crit Care Med 2020 12;21(12):1033-1034

Emeritus Editor, Pediatric Critical Care Medicine Distinguished Professor of Critical Care Medicine Ake N. Grenvik Professor of Critical Care Medicine Vice Chair, Department of Critical Care Medicine Professor of Anesthesiology, Pediatrics, Bioengineering, and Clinical and Translational Science Director, Safar Center for Resuscitation Research UPMC Children's Hospital of Pittsburgh.

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http://dx.doi.org/10.1097/PCC.0000000000002613DOI Listing
December 2020

(Sulfonylurea Receptor-1) Impact on Brain Atrophy after Traumatic Brain Injury Varies by Sex.

J Neurotrauma 2021 Sep 25;38(17):2473-2485. Epub 2021 Jun 25.

Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA.

Females have been understudied in pre-clinical and clinical traumatic brain injury (TBI), despite distinct biology and worse clinical outcomes versus males. Sulfonylurea receptor 1 (SUR1) inhibition has shown promising results in predominantly male TBI. A phase II trial is ongoing. We investigated whether SUR1 inhibition effects on contusional TBI differ by sex given that this may inform clinical trial design and/or interpretation. We studied the moderating effects of sex on post-injury brain tissue loss in 142 male and female ATP-binding cassette transporter subfamily C member 8 () wild-type, heterozygote, and knockout mice (12-15 weeks). Monkey fibroblast-like cells and mouse brain endothelium-derived cells were used for studies. Mice were injured with controlled cortical impact and euthanized 21 days post-injury to assess contusion, brain, and hemisphere volumes (vs. genotype- and sex-matched naïves). knockout mice had smaller contusion volumes ( = 0.012) and larger normalized contralateral (right) hemisphere volumes (nRHV;  = 0.03) after injury versus wild type. This was moderated by sex: Contusions were smaller ( = 0.020), nRHV was higher ( = 0.001), and there was less global atrophy ( = 0.003) in male, but not female, knockout versus wild-type mice after TBI. Less atrophy occurred in males for each copy of lost ( = 0.023-0.002, all outcomes). , sex-determining region Y (SRY) stimulated promoter activity and increased expression. Loss of strongly protected against post-traumatic cerebral atrophy in male, but not female, mice. This may partly be mediated by SRY on the Y-chromosome. Sex differences may have important implications for ongoing and future trials of SUR1 blockade.
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http://dx.doi.org/10.1089/neu.2021.0105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403186PMC
September 2021

Ascorbate deficiency confers resistance to hippocampal neurodegeneration after asphyxial cardiac arrest in juvenile rats.

Pediatr Res 2021 Apr 12. Epub 2021 Apr 12.

Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Background: Asphyxial cardiac arrest (CA) is a significant cause of death and disability in children. Using juvenile Osteogenic disorder Shionogi (ODS) rats that, like humans, do not synthesize ascorbate, we tested the effect of ascorbate deficiency on functional and histological outcome after CA.

Methods: Postnatal day 16-18 milk-fed ODS and wild-type Wistar rats underwent 9-min asphyxial CA (n = 8/group) or sham surgery (n = 4/group). ODS mothers received ascorbate in drinking water to prevent scurvy. Levels of ascorbate and glutathione (GSH) were measured in plasma and hippocampus at baseline and after CA. Neurologic deficit score (NDS) was measured at 3, 24, and 48 h and hippocampal neuronal counts, neurodegeneration, and microglial activation were assessed at day 7.

Results: ODS rats showed depletion of plasma and hippocampal ascorbate, attenuated hippocampal neurodegeneration and microglial activation, and increased CA1 hippocampal neuron survival vs. Wistar rats while NDS were similar. Hippocampal GSH levels were higher in ODS vs. Wistar rats at baseline and 10 min, whereas hypoxia-inducible factor-1α levels were higher in Wistar vs. ODS rats at 24 , after CA.

Conclusion: Ascorbate-deficient juvenile ODS rats appear resistant to neurodegeneration produced by asphyxia CA, possibly related to upregulation of the endogenous antioxidant GSH in brain.

Impact: Like humans and unlike other rodents, osteogenic disorder Shionogi (ODS) rats do not synthesize ascorbate, and thus may serve as a useful model for studying the role of ascorbate in human disease. Conflicting evidence exists regarding ascorbate's protective versus detrimental effects in animal models and clinical studies. Ascorbate-deficient ODS rats are resistant to neurodegeneration after experimental cardiac arrest.
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http://dx.doi.org/10.1038/s41390-021-01515-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505544PMC
April 2021

Kollidon VA64 Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

J Neurotrauma 2021 Sep 14;38(17):2454-2472. Epub 2021 May 14.

Department of Neurological Surgery, Brain Trauma Research Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Loss of plasmalemmal integrity may mediate cell death after traumatic brain injury (TBI). Prior studies in controlled cortical impact (CCI) indicated that the membrane resealing agent Kollidon VA64 improved histopathological and functional outcomes. Kollidon VA64 was therefore selected as the seventh therapy tested by the Operation Brain Trauma Therapy consortium, across three pre-clinical TBI rat models: parasagittal fluid percussion injury (FPI), CCI, and penetrating ballistic-like brain injury (PBBI). In each model, rats were randomized to one of four exposures (7-15/group): (1) sham; (2) TBI+vehicle; (3) TBI+Kollidon VA64 low-dose (0.4 g/kg); and (4) TBI+Kollidon VA64 high-dose (0.8 g/kg). A single intravenous VA64 bolus was given 15 min post-injury. Behavioral, histopathological, and serum biomarker outcomes were assessed over 21 days generating a 22-point scoring matrix per model. In FPI, low-dose VA64 produced zero points across behavior and histopathology. High-dose VA64 worsened motor performance compared with TBI-vehicle, producing -2.5 points. In CCI, low-dose VA64 produced intermediate benefit on beam balance and the Morris water maze (MWM), generating +3.5 points, whereas high-dose VA64 showed no effects on behavior or histopathology. In PBBI, neither dose altered behavior or histopathology. Regarding biomarkers, significant increases in glial fibrillary acidic protein (GFAP) levels were seen in TBI versus sham at 4 h and 24 h across models. Benefit of low-dose VA64 on GFAP was seen at 24 h only in FPI. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) was increased in TBI compared with vehicle across models at 4 h but not at 24 h, without treatment effects. Overall, low dose VA64 generated +4.5 points (+3.5 in CCI) whereas high dose generated -2.0 points. The modest/inconsistent benefit observed reduced enthusiasm to pursue further testing.
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http://dx.doi.org/10.1089/neu.2021.0089DOI Listing
September 2021

Serum Biomarkers of Regeneration and Plasticity are Associated with Functional Outcome in Pediatric Neurocritical Illness: An Exploratory Study.

Neurocrit Care 2021 Mar 4. Epub 2021 Mar 4.

Department of Critical Care Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

Background/objective: Pediatric neurocritical care survivorship is frequently accompanied by functional impairments. Lack of prognostic biomarkers is a barrier to early identification and management of impairment. We explored the association between blood biomarkers and functional impairment in children with acute acquired brain injury.

Methods: This study is a secondary analysis of a randomized control trial evaluating early versus usual care rehabilitation in the pediatric intensive care unit (PICU). Forty-four children (17 [39%] female, median age 11 [interquartile range 6-13] years) with acute acquired brain injury admitted to the PICU were studied. A single center obtained serum samples on admission days 0, 1, 3, 5, and the day closest to hospital discharge. Biomarkers relevant to brain injury (neuron specific enolase [NSE], S100b), inflammation (interleukin [IL-6], C-reactive protein), and regeneration (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor [VEGF]) were collected. Biomarkers were analyzed using a Luminex® bioassay. Functional status scale (FSS) scores were abstracted from the medical record. New functional impairment was defined as a (worse) FSS score at hospital discharge compared to pre-PICU (baseline). Individual biomarker fluorescence index (FI) values for each sample collection day were correlated with new functional impairment using Spearman rank correlation coefficient (ρ). Trends in repeated measures of biomarker FI over time were explored graphically, and the association between repeated measures of biomarker FI and new functional impairment was analyzed using covariate adjusted linear mixed-effect models.

Results: Functional impairment was inversely correlated with markers of regeneration and plasticity including BDNF at day 3 (ρ =  - 0.404, p = .015), day 5 (ρ =  - 0.549, p = 0.005) and hospital discharge (ρ =  - 0.420, p = 0.026) and VEGF at day 1 (ρ =  - 0.282, p = 0.008) and hospital discharge (ρ =  - 0.378, p = 0.047), such that lower levels of both markers at each time point were associated with greater impairment. Similarly, repeated measures of BDNF and VEGF were inversely correlated with new functional impairment (B =  - 0.001, p = 0.001 and B =  - 0.001, p = 0.003, respectively). NSE, a biomarker of acute brain injury, showed a positive correlation between day 0 levels and new functional impairment (ρ = 0.320, p = 0.044).

Conclusions: Blood-based biomarkers of regeneration and plasticity may hold prognostic utility for functional impairment among pediatric patients with neurocritical illness and warrant further investigation.
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http://dx.doi.org/10.1007/s12028-021-01199-zDOI Listing
March 2021

Cardiac Arrest Induced by Asphyxia Versus Ventricular Fibrillation Elicits Comparable Early Changes in Cytokine Levels in the Rat Brain, Heart, and Serum.

J Am Heart Assoc 2021 02 18;10(5):e018657. Epub 2021 Feb 18.

Safar Center for Resuscitation ResearchUniversity of Pittsburgh School of Medicine Pittsburgh PA.

Background Current postresuscitative care after cardiac arrest (CA) does not address the cause of CA. We previously reported that asphyxial CA (ACA) and ventricular fibrillation CA (VFCA) elicit unique injury signatures. We hypothesized that the early cytokine profiles of the serum, heart, and brain differ in response to ACA versus VFCA. Methods and Results Adult male rats were subjected to 10 minutes of either ACA or VFCA. Naives and shams (anesthesia and surgery without CA) served as controls (n=12/group). Asphyxiation produced an ≈4-minute period of progressive hypoxemia followed by a no-flow duration of ≈6±1 minute. Ventricular fibrillation immediately induced no flow. Return of spontaneous circulation was achieved earlier after ACA compared with VFCA (42±18 versus 105±22 seconds; <0.001). Brain cytokines in naives were, in general, low or undetectable. Shams exhibited a modest effect on select cytokines. Both ACA and VFCA resulted in robust cytokine responses in serum, heart, and brain at 3 hours. Significant regional differences pinpointed the striatum as a key location of neuroinflammation. No significant differences in cytokines, neuron-specific enolase, S100b, and troponin T were observed across CA models. Conclusions Both models of CA resulted in marked systemic, heart, and brain cytokine responses, with similar degrees of change across the 2 CA insults. Changes in cytokine levels after CA were most pronounced in the striatum compared with other brain regions. These collective observations suggest that the amplitude of the changes in cytokine levels after ACA versus VFCA may not mediate the differences in secondary injuries between these 2 CA phenotypes.
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http://dx.doi.org/10.1161/JAHA.120.018657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174297PMC
February 2021

Operation Brain Trauma Therapy: An Exploratory Study of Levetiracetam Treatment Following Mild Traumatic Brain Injury in the Micro Pig.

Front Neurol 2020 13;11:586958. Epub 2021 Jan 13.

Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.

Operation brain trauma therapy (OBTT) is a drug- and biomarker-screening consortium intended to improve the quality of preclinical studies and provide a rigorous framework to increase the translational potential of experimental traumatic brain injury (TBI) treatments. Levetiracetam (LEV) is an antiepileptic agent that was the fifth drug tested by OBTT in three independent rodent models of moderate to severe TBI. To date, LEV has been the most promising drug tested by OBTT and was therefore advanced to testing in the pig. Adult male micro pigs were subjected to a mild central fluid percussion brain injury followed by a post-injury intravenous infusion of either 170 mg/kg LEV or vehicle. Systemic physiology was assessed throughout the post-injury period. Serial serum samples were obtained pre-injury as well as at 1 min, 30 min, 1 h, 3 h, and 6 h post-injury for a detailed analysis of the astroglial biomarker glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1. Tissue was collected 6 h following injury for histological assessment of diffuse axonal injury using antibodies against the amyloid precursor protein (APP). The animals showed significant increases in circulating GFAP levels from baseline to 6 h post-injury; however, LEV treatment was associated with greater GFAP increases compared to the vehicle. There were no differences in the numbers of APP+ axonal swellings within the pig thalamus with LEV treatment; however, significant alterations in the morphological properties of the APP+ axonal swellings, including reduced swelling area and increased swelling roundness, were observed. Additionally, expression of the neurite outgrowth marker, growth-associated protein 43, was reduced in axonal swellings following LEV treatment, suggesting potential effects on axonal outgrowth that warrant further investigation.
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http://dx.doi.org/10.3389/fneur.2020.586958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874167PMC
January 2021

Addressing Key Clinical Care and Clinical Research Needs in Severe Pediatric Traumatic Brain Injury: Perspectives From a Focused International Conference.

Front Pediatr 2020 18;8:594425. Epub 2021 Jan 18.

Department of Critical Care Medicine, Safar Center for Resuscitation Research, John G Rangos Research Center, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in children and adolescents. Survivors of severe TBI are more prone to functional deficits, resulting in poorer school performance, poor health-related quality of life (HRQoL), and increased risk of mental health problems. Critical gaps in knowledge of pathophysiological differences between children and adults concerning TBI outcomes, the paucity of pediatric trials and prognostic models and the uncertain extrapolation of adult data to pediatrics pose significant challenges and demand global efforts. Here, we explore the clinical and research unmet needs focusing on severe pediatric TBI to identify best practices in pathways of care and optimize both inpatient and outpatient management of children following TBI.
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http://dx.doi.org/10.3389/fped.2020.594425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849211PMC
January 2021

Cerebrospinal Fluid Sulfonylurea Receptor-1 is Associated with Intracranial Pressure and Outcome after Pediatric TBI: An Exploratory Analysis of the Cool Kids Trial.

J Neurotrauma 2021 Jun 16;38(12):1615-1619. Epub 2021 Feb 16.

Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Sulfonylurea receptor-1 (SUR1) is recognized increasingly as a key contributor to cerebral edema, hemorrhage progression, and possibly neuronal death in multiple forms of acute brain injury. SUR1 inhibition may be protective and is actively undergoing evaluation in Phase-2/3 trials of traumatic brain injury (TBI) and stroke. In adult TBI, SUR1 expression is associated with intracranial hypertension and contusion expansion; its role in pediatric TBI remains unexplored. We tested 61 cerebrospinal fluid (CSF) samples from 16 pediatric patients with severe TBI enrolled in the multicenter Phase-3 randomized controlled "Cool Kids" trial and seven non-brain injured pediatric controls for SUR1 expression by enzyme-linked immunosorbent assay. Linear mixed models evaluated associations between mean SUR1 and intracranial pressure (ICP) over the first seven days and pediatric Glasgow Outcome Scale-Extended (GOS-E Peds) over the initial year after injury. SUR1 was undetectable in control CSF and increased versus control in nine of 16 patients with TBI. Mean SUR1 was not associated with age, sex, or therapeutic hypothermia. Each 1-point increase in initial Glasgow Coma Score was associated with a 1.68 ng/mL decrease in CSF SUR1. The CSF SUR1 was associated with increased ICP over seven days (b = 0.73,  = 0.004) and worse (higher) GOS-E Peds score (b = 0.24,  = 0.004). In this exploratory pediatric study, CSF SUR1 was undetectable in controls and variably elevated in severe TBI. Mean CSF SUR1 concentration was associated with ICP and outcome. These findings are distinct from our previous report in adults with severe TBI, where SUR1 was detected universally. SUR1 may be a viable therapeutic target in a subset of pediatric TBI, and further study is warranted.
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http://dx.doi.org/10.1089/neu.2020.7501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165477PMC
June 2021

Hippocampal and Prefrontal Cortical Brain Tissue Levels of Irisin and GDF15 Receptor Subunits in Children.

Mol Neurobiol 2021 May 7;58(5):2145-2157. Epub 2021 Jan 7.

School of Medicine, Children's Hospital of Pittsburgh of UPMC, Safar Center for Resuscitation Research, University of Pittsburgh, John G. Rangos Research Center - 6th Floor, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.

Cold-stress hormones (CSHs) stimulate thermogenesis and have direct neuroprotective effects on the brain. The obligatory receptor components of two new CSHs (irisin and growth differentiation factor-15 [GDF15]) were recently discovered. Irisin binds integrin-αV/β5 heterodimers while GDF-15 binds to the orphan receptor glial cell-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL). In addition, integrin-αV/β5 was just identified as the key receptor mediating Zika virus infection in the CNS. We measured integrin-αV, integrin-β5, and GFRAL protein levels across 78 high-quality human male/female brain tissues in infants, toddlers, preschoolers, adolescent, and adults-providing the most robust analysis to date on their levels in the human cortex and hippocampus. We report that integrin-αV was detected at all ages in the prefrontal cortex with levels greatest in adults. Integrin-αV was also detected in the hippocampus in all age groups. In contrast, integrin-β5 was detected in cortex and hippocampus largely restricted to infants. Co-expression of integrin-αV/β5 in the human infant hippocampus and cortex suggests the possibility that irisin has a more robust effect on the developing vs. the adult brain and may have implications for Zika virus infection in infants and young children.
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http://dx.doi.org/10.1007/s12035-020-02250-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788542PMC
May 2021

Strengthening the link between pre-clinical and clinical resuscitation research.

Resuscitation 2021 01 27;158:282-285. Epub 2020 Nov 27.

Safar Center for Resuscitation Research, United States; Department of Emergency Medicine, United States; University of Pittsburgh School of Medicine, United States.

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http://dx.doi.org/10.1016/j.resuscitation.2020.11.008DOI Listing
January 2021

Intracranial and Cerebral Perfusion Pressure Thresholds Associated With Inhospital Mortality Across Pediatric Neurocritical Care.

Pediatr Crit Care Med 2021 02;22(2):135-146

Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Objectives: Targets for treatment of raised intracranial pressure or decreased cerebral perfusion pressure in pediatric neurocritical care are not well defined. Current pediatric guidelines, based on traumatic brain injury, suggest an intracranial pressure target of less than 20 mm Hg and cerebral perfusion pressure minimum of 40-50 mm Hg, with possible age dependence of cerebral perfusion pressure. We sought to define intracranial pressure and cerebral perfusion pressure thresholds associated with inhospital mortality across a large single-center pediatric neurocritical care cohort.

Design: Retrospective chart review.

Setting: PICU, single quaternary-care center.

Patients: Individuals receiving intracranial pressure monitoring from January 2012 to December 2016.

Interventions: None.

Measurements And Main Results: Intracranial pressure and cerebral perfusion pressure measurements from 262 neurocritical care patients (87 traumatic brain injury and 175 nontraumatic brain injury; 63% male; 8.3 ± 5.8 yr; mortality 11.1%). Mean intracranial pressure and cerebral perfusion pressure had area under the receiver operating characteristic curves of 0.75 and 0.64, respectively, for association of inhospital mortality. Cerebral perfusion pressure cut points increased with age (< 2 yr = 47, 2 to < 8 yr = 58 mm Hg, ≥ 8 yr = 73 mm Hg). In the traumatic brain injury subset, mean intracranial pressure and cerebral perfusion pressure had area under the receiver operating characteristic curves of 0.70 and 0.78, respectively, for association of inhospital mortality. Traumatic brain injury cerebral perfusion pressure cut points increased with age (< 2 yr = 45, 2 to < 8 yr = 57, ≥ 8 yr = 68 mm Hg). Mean intracranial pressure greater than 15 mm Hg, male sex, and traumatic brain injury status were independently associated with inhospital mortality (odds ratio, 14.23 [5.55-36.46], 2.77 [1.04-7.39], and 2.57 [1.03-6.38], respectively; all p < 0.05). Mean cerebral perfusion pressure less than 67 mm Hg and traumatic brain injury status were independently associated with inhospital mortality (odds ratio, 5.16 [2.05-12.98] and 3.71 [1.55-8.91], respectively; both p < 0.01). In the nontraumatic brain injury subset, mean intracranial pressure had an area under the receiver operating characteristic curve 0.77 with an intracranial pressure cut point of 15 mm Hg, whereas mean cerebral perfusion pressure was not predictive of inhospital mortality.

Conclusions: We identified mean intracranial pressure thresholds, utilizing receiver operating characteristic and regression analyses, associated with inhospital mortality that is below current guidelines-based treatment targets in both traumatic brain injury and nontraumatic brain injury patients, and age-dependent cerebral perfusion pressure thresholds associated with inhospital mortality that were above current guidelines-based targets in traumatic brain injury patients. Further study is warranted to identify data-driven intracranial pressure and cerebral perfusion pressure targets in children undergoing intracranial pressure monitoring, whether for traumatic brain injury or other indications.
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http://dx.doi.org/10.1097/PCC.0000000000002618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855782PMC
February 2021

Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

J Neurotrauma 2021 03 18;38(5):628-645. Epub 2020 Dec 18.

Safar Center for Resuscitation Research, Department of Critical Care Medicine, Anesthesiology, and Clinical and Translational Science, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Glibenclamide (GLY) is the sixth drug tested by the Operation Brain Trauma Therapy (OBTT) consortium based on substantial pre-clinical evidence of benefit in traumatic brain injury (TBI). Adult Sprague-Dawley rats underwent fluid percussion injury (FPI;  = 45), controlled cortical impact (CCI;  = 30), or penetrating ballistic-like brain injury (PBBI;  = 36). Efficacy of GLY treatment (10-μg/kg intraperitoneal loading dose at 10 min post-injury, followed by a continuous 7-day subcutaneous infusion [0.2 μg/h]) on motor, cognitive, neuropathological, and biomarker outcomes was assessed across models. GLY improved motor outcome versus vehicle in FPI (cylinder task,  < 0.05) and CCI (beam balance,  < 0.05; beam walk,  < 0.05). In FPI, GLY did not benefit any other outcome, whereas in CCI, it reduced 21-day lesion volume versus vehicle ( < 0.05). On Morris water maze testing in CCI, GLY worsened performance on hidden platform latency testing versus sham ( < 0.05), but not versus TBI vehicle. In PBBI, GLY did not improve any outcome. Blood levels of glial fibrillary acidic protein and ubiquitin carboxyl terminal hydrolase-1 at 24 h did not show significant treatment-induced changes. In summary, GLY showed the greatest benefit in CCI, with positive effects on motor and neuropathological outcomes. GLY is the second-highest-scoring agent overall tested by OBTT and the only drug to reduce lesion volume after CCI. Our findings suggest that leveraging the use of a TBI model-based phenotype to guide treatment (i.e., GLY in contusion) might represent a strategic choice to accelerate drug development in clinical trials and, ultimately, achieve precision medicine in TBI.
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http://dx.doi.org/10.1089/neu.2020.7421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418525PMC
March 2021

Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients.

J Neurotrauma 2021 01 11;38(1):1-43. Epub 2020 Nov 11.

Banyan Biomarkers Inc., Alachua, Florida, USA.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus attacks multiple organs of coronavirus disease 2019 (COVID-19) patients, including the brain. There are worldwide descriptions of neurological deficits in COVID-19 patients. Central nervous system (CNS) symptoms can be present early in the course of the disease. As many as 55% of hospitalized COVID-19 patients have been reported to have neurological disturbances three months after infection by SARS-CoV-2. The mutability of the SARS-COV-2 virus and its potential to directly affect the CNS highlight the urgency of developing technology to diagnose, manage, and treat brain injury in COVID-19 patients. The pathobiology of CNS infection by SARS-CoV-2 and the associated neurological sequelae of this infection remain poorly understood. In this review, we outline the rationale for the use of blood biomarkers (BBs) for diagnosis of brain injury in COVID-19 patients, the research needed to incorporate their use into clinical practice, and the improvements in patient management and outcomes that can result. BBs of brain injury could potentially provide tools for detection of brain injury in COVID-19 patients. Elevations of BBs have been reported in cerebrospinal fluid (CSF) and blood of COVID-19 patients. BB proteins have been analyzed in CSF to detect CNS involvement in patients with infectious diseases, including human immunodeficiency virus and tuberculous meningitis. BBs are approved by the U.S. Food and Drug Administration for diagnosis of mild versus moderate traumatic brain injury and have identified brain injury after stroke, cardiac arrest, hypoxia, and epilepsy. BBs, integrated with other diagnostic tools, could enhance understanding of viral mechanisms of brain injury, predict severity of neurological deficits, guide triage of patients and assignment to appropriate medical pathways, and assess efficacy of therapeutic interventions in COVID-19 patients.
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http://dx.doi.org/10.1089/neu.2020.7332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757533PMC
January 2021

Personalising Outcomes after Child Cardiac Arrest (POCCA): design and recruitment challenges of a multicentre, observational study.

BMJ Open 2020 10 27;10(10):e039323. Epub 2020 Oct 27.

Epidemiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Introduction: Blood and imaging biomarkers show promise in prognosticating outcomes after paediatric cardiac arrest in pilot studies. We describe the methods and early recruitment challenges and solutions for an ongoing multicentre (n=14) observational trial, Personalising Outcomes following Child Cardiac Arrest to validate clinical, blood and imaging biomarkers individually and together in a clinically relevant panel.

Methods And Analysis: Children (n=164) between 48 hours and 17 years of age who receive chest compressions irrespective of provider, duration, or event location and are admitted to an intensive care unit are eligible. Blood samples will be taken on days 1-3 for the measurement of brain-focused biomarkers analysed to predict the outcome. Clinically indicated and timed brain MRI and spectroscopy biomarkers will be analysed to predict the outcome. The primary outcome for the trial is survival with favourable (Vineland Adaptive Behavioural Scale score >70) outcome at 1 year. Secondary outcomes include mortality and pre-event and postdischarge measures of emotional, cognitive, physical and family functioning and health-related quality of life. Early enrollment targets were not met due to prolonged regulatory and subcontract processes. Multiple, simultaneous interventions including modification to inclusion criteria, additional sites and site visits were implemented with successful improvement in recruitment. Study procedures including outcomes and biomarker analysis are ongoing.

Ethics And Dissemination: Twelve of 14 sites will use the centralised Institutional Review Board (IRB) at the University of Pittsburgh (PRO14030712). Two sites will use individual IRBs: Children's Healthcare of Atlanta Institutional Review Board and Children's Hospital of Wisconsin IRB. Parents and/or guardians are consented and children assented (when possible) by the site Primary investigator (PI) or research coordinator for enrollment. Study findings will be disseminated through scientific conferences, peer-reviewed journal publications, public study website materials and invited lectures.

Trial Registration Number: NCT02769026.
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http://dx.doi.org/10.1136/bmjopen-2020-039323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592297PMC
October 2020

Prehospital Whole Blood Resuscitation Reduces Fluid Requirement While Maintaining Critical Physiology in a Model of Penetrating Traumatic Brain Injury and Hemorrhage: Implications on Resource-Limited Combat Casualty Care.

Shock 2021 04;55(4):545-553

Safar Center for Resuscitation Research, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Abstract: Prehospital resuscitation using whole blood (WB) is the standard of care for hemorrhagic shock (HS) but there is no consensus recommendation for resuscitation in the presence of traumatic brain injury (TBI) due to a lack of sufficient evidence. In order to evaluate the optimal resuscitation strategies for TBI+HS, Sprague-Dawley rats were randomized into four groups based on resuscitation fluid and prehospital mean arterial pressure (MAP) threshold (n = 9-10/group): Lactated Ringer's (LR)-60 mm Hg (LR60), LR-70 mm Hg (LR70), WB-60 mm Hg (WB60), WB-70 mm Hg (WB70). All groups received a frontal penetrating ballistic-like brain injury followed by a 35-min period of HS. During the prehospital phase, rats received an initial bolus of resuscitation fluid (WB or LR) followed by LR as needed to maintain MAP above the designated threshold for 90 min. During the in-hospital phase, rats received definitive resuscitation with shed WB. Physiological parameters were recorded continuously and cerebral edema was measured at 3 and 24 h postinjury. The WB60 group demonstrated a significantly lower prehospital fluid requirement compared WB70, LR60, and LR70 (P < 0.05). Compared to the respective LR groups, both the WB60 and WB70 groups also demonstrated improved MAP, cerebral perfusion pressure, brain tissue oxygen tension, and cerebral edema. The edema benefits were observed at 3 h, but not 24 h postinjury, and were localized to the injury site. Together, these results provide evidence that prehospital WB resuscitation and lower MAP resuscitation thresholds can reduce the prehospital fluid requirement while still maintaining critical cerebral physiology in a model of HS and concomitant TBI.
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http://dx.doi.org/10.1097/SHK.0000000000001662DOI Listing
April 2021

Multifaceted Benefit of Whole Blood Versus Lactated Ringer's Resuscitation After Traumatic Brain Injury and Hemorrhagic Shock in Mice.

Neurocrit Care 2021 06 4;34(3):781-794. Epub 2020 Sep 4.

Clinical and Translational Science Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Background: Despite increasing use in hemorrhagic shock (HS), whole blood (WB) resuscitation for polytrauma with traumatic brain injury (TBI) is largely unexplored. Current TBI guidelines recommend crystalloid for prehospital resuscitation. Although WB outperforms lactated Ringer's (LR) in increasing mean arterial pressure (MAP) in TBI + HS models, effects on brain tissue oxygenation (PbtO), and optimal MAP remain undefined.

Methods: C57BL/6 mice (n = 72) underwent controlled cortical impact followed by HS (MAP = 25-27 mmHg). Ipsilateral hippocampal PbtO (n = 40) was measured by microelectrode. Mice were assigned to four groups (n = 18/group) for "prehospital" resuscitation (90 min) with LR or autologous WB, and target MAPs of 60 or 70 mmHg (LR, WB, LR, WB). Additional LR (10 ml/kg) was bolused every 5 min for MAP below target.

Results: LR requirements in WB (7.2 ± 5.0 mL/kg) and WB (28.3 ± 9.6 mL/kg) were markedly lower than in LR (132.8 ± 5.8 mL/kg) or LR (152.2 ± 4.8 mL/kg; all p < 0.001). WB MAP (72.5 ± 2.9 mmHg) was higher than LR (59.8 ± 4.0 mmHg, p < 0.001). WB MAP (68.7 ± 4.6 mmHg) was higher than LR (53.5 ± 3.2 mmHg, p < 0.001). PbtO was higher in WB (43.8 ± 11.6 mmHg) vs either LR (25.9 ± 13.0 mmHg, p = 0.04) or LR (24.1 ± 8.1 mmHg, p = 0.001). PbtO in WB (40.7 ± 8.8 mmHg) was higher than in LR (p = 0.007). Despite higher MAP in WB vs WB (p = .002), PbtO was similar.

Conclusion: WB resuscitation after TBI + HS results in robust improvements in brain oxygenation while minimizing fluid volume when compared to standard LR resuscitation. WB resuscitation may allow for a lower prehospital MAP without compromising brain oxygenation when compared to LR resuscitation. Further studies evaluating the effects of these physiologic benefits on outcome after TBI with HS are warranted, to eventually inform clinical trials.
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http://dx.doi.org/10.1007/s12028-020-01084-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054986PMC
June 2021

Depletion of gut microbiota is associated with improved neurologic outcome following traumatic brain injury.

Brain Res 2020 11 13;1747:147056. Epub 2020 Aug 13.

Departments of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Departments of Center for Microbiome and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Departments of Environmental and Occupational Health, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Signaling between intestinal microbiota and the brain influences neurologic outcome in multiple forms of brain injury. The impact of gut microbiota following traumatic brain injury (TBI) has not been well established. Our objective was to compare TBI outcomes in specific pathogen-free mice with or without depletion of intestinal bacteria. Adult male C57BL6/J SPF mice (n = 6/group) were randomized to standard drinking water or ampicillin (1 g/L), metronidazole (1 g/L), neomycin (1 g/L), and vancomycin (0.5 g/L) (AMNV) containing drinking water 14 days prior to controlled cortical impact (CCI) model of TBI. 16S rRNA gene sequencing of fecal pellets was performed and alpha and beta diversity determined. Hippocampal neuronal density and microglial activation was assessed 72 h post-injury by immunohistochemistry. In addition, mice (n = 8-12/group) were randomized to AMNV or no treatment initiated immediately after CCI and memory acquisition (fear conditioning) and lesion volume assessed. Mice receiving AMNV had significantly reduced alpha diversity (p < 0.05) and altered microbiota community composition compared to untreated mice (PERMANOVA: p < 0.01). Mice receiving AMNV prior to TBI had increased CA1 hippocampal neuronal density (15.2 ± 1.4 vs. 8.8 ± 2.1 cells/0.1 mm; p < 0.05) and a 26.6 ± 6.6% reduction in Iba-1 positive cells (p < 0.05) at 72 h. Mice randomized to AMNV immediately after CCI had attenuated associative learning deficit on fear conditioning test (%freeze Cue: 63.7 ± 2.7% vs. 41.0 ± 5.1%, p < 0.05) and decreased lesion volume (27.2 ± 0.8 vs. 24.6 ± 0.7 mm, p < 0.05). In conclusion, depletion of intestinal microbiota was consistent with a neuroprotective effect whether initiated before or after injury in a murine model of TBI. Further investigations of the role of gut microbiota in TBI are warranted.
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http://dx.doi.org/10.1016/j.brainres.2020.147056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521107PMC
November 2020
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