Preserving brain LPC‐DHA by plasma supplementation attenuates brain injury after cardiac arrest

Blood-based brain injury biomarkers show promise to prognosticate outcome for children resuscitated from cardiac arrest. The objective of this multicenter, observational study was to validate promising biomarkers to accurately prognosticate outcome at 1 year. Early brain injury biomarkers will be associated with outcome at one year for children with cardiac arrest. Fourteen centers in the US enrolled children aged < 18 years with in- or out-of-hospital cardiac arrest and pediatric intensive care unit admission if pre-cardiac arrest Pediatric Cerebral Performance Category score was 1-3. Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal esterase L1 (UCHL1), neurofilament light (NfL), and Tau protein concentrations were measured in samples drawn post-arrest day 1 using Quanterix Simoa 4-Plex assay. The primary outcome was unfavorable outcome at one year (Vineland Adaptive Behavioral Scale < 70). Of 164 children enrolled, 120 children had evaluable data (n=50 with unfavorable outcome). Children were median (interquartile range) 1 (0-8.5) years of age, 41% female, and 60% had asphyxia etiology. Of children with unfavorable outcome, 93% had unwitnessed arrests and 43 died. While all 4 day 1 biomarkers were increased in children with unfavorable vs. favorable outcome at 1-year post-arrest, NfL had the best univariate area under the receiver operator curve to predict 1 year outcome at 0.731. In a multivariate logistic regression, NfL concentration trended toward significance on day 1 and was associated with unfavorable outcome at 1-year on days 2 and 3 (day 1: Odds Ratio [95% Confidence Interval] 1.004 [1.000-1.008], p=.062; day 2: 1.005 [1.002-1.008], p=.003, and day 3: 1.002 [1.001-1.004], p=.003, respectively). UCHL1 was associated with outcome on days 2: 1.005 [1.002-1.009], p=.003 and 3: 1.001 [1.000-1.002], p=.019) and Tau trended toward association with outcome on days 2: 1.003 [1.000-1.005], p=.08) and 3: 1.001 [1.000-1.002], p=.077. Brain injury biomarkers predict unfavorable outcome post-pediatric cardiac arrest. Accuracy of biomarkers alone and together with other prognostication tools should be evaluated to predict long term child centered outcomes post-cardiac arrest.

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Abstract 273: Noninvasive Mitochondrial Modulation: Neuroprotection in a Translational Model of Cardiac Arrest and Resuscitation

Circulation ◽

10.1161/circ.140.suppl_2.273 ◽

2019 ◽

Vol 140 (Suppl_2) ◽

Author(s):

Joseph M Wider ◽

Erin Gruley ◽

Jennifer Mathieu ◽

Emma Murphy ◽

Rachel Mount ◽

...

Keyword(s):

Cardiac Arrest ◽

Brain Injury ◽

Near Infrared ◽

Small Animal ◽

Spontaneous Circulation ◽

Infrared Light ◽

Swine Model ◽

Treatment Groups ◽

The Brain ◽

Neuroprotective Therapies

Background: Mitochondrial dysfunction contributes to cardiac arrest induced brain injury and has been a target for neuroprotective therapies. An emerging concept suggests that hyperactivation of neuronal mitochondria following resuscitation results in hyperpolarization of the mitochondrial membrane during reperfusion, which drives generation of excess reactive oxygen species. Previous studies from our group demonstrated that limiting mitochondrial hyperactivity by non-invasively modulating mitochondrial function with specific near infrared light (NIR) wavelengths can reduce brain injury in small animal models of global and focal ischemia. Hypothesis: Inhibitory wavelengths of NIR will reduce neuronal injury and improve neurocognitive outcome in a clinically relevant swine model of cardiac arrest. Methods: Twenty-eight male and female adult swine were enrolled (3 groups: Sham, CA/CPR, and CA/CPR + NIR). Cardiac arrest (8 minutes) was induced with a ventricular pacing wire and followed by manual CPR with defibrillation and epinephrine every 30 seconds until return of spontaneous circulation (ROSC), 2 of the 20 swine that underwent CA did not achieve ROSC and were not enrolled. Treatment groups were randomized prior to arrest and blinded to the CPR team. Treatment was applied at onset of ROSC by irradiating the scalp with 750 nm and 950 nm LEDs (5W) for 2 hours. Results: Sham-operated animals all survived (8/8), whereas 22% of untreated animals subjected to cardiac arrest died within 45 min of ROSC (CA/CPR, n= 7/9). All swine treated with NIR survived the duration of the study (CA/CPR + NIR, n=9/9). Four days following cardiac arrest, neurological deficit score was improved in the NIR treatment group (50 ± 21 CA/CPR vs. 0.8 ± 0.8 CA/CPR + NIR, p < 0.05). Additionally, neuronal death in the CA1/CA3 regions of the hippocampus, assessed by counting surviving neurons with stereology, was attenuated by treatment with NIR (17917 ± 5534 neurons/mm 3 CA/CPR vs. 44655 ± 5637 neurons/mm 3 CA/CPR + NIR, p < 0.05). All data is reported as mean ± SEM. Conclusions: These data provide evidence that noninvasive modulation of mitochondria, achieved by transcranial irradiation of the brain with NIR, mitigates post-cardiac arrest brain injury.

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Electroacupuncture pretreatment attenuates brain injury in a mouse model of cardiac arrest and cardiopulmonary resuscitation via the AKT/eNOS pathway

Life Sciences ◽

10.1016/j.lfs.2019.116821 ◽

2019 ◽

Vol 235 ◽

pp. 116821 ◽

Cited By ~ 2

Author(s):

Yue Yong ◽

Jun Guo ◽

Dongyu Zheng ◽

Yonghua Li ◽

Wei Chen ◽

...

Keyword(s):

Cardiac Arrest ◽

Brain Injury ◽

Cardiopulmonary Resuscitation ◽

Mouse Model

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Optimizing Stem Cell Therapy after Ischemic Brain Injury

Journal of Stroke ◽

10.5853/jos.2019.03048 ◽

2020 ◽

Vol 22 (3) ◽

pp. 286-305 ◽

Cited By ~ 1

Author(s):

Shuai Zhang ◽

Brittany Bolduc Lachance ◽

Bilal Moiz ◽

Xiaofeng Jia

Keyword(s):

Stem Cells ◽

Clinical Trials ◽

Cardiac Arrest ◽

Stem Cell ◽

Brain Injury ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Injury Treatment

Stem cells have been used for regenerative and therapeutic purposes in a variety of diseases. In ischemic brain injury, preclinical studies have been promising, but have failed to translate results to clinical trials. We aimed to explore the application of stem cells after ischemic brain injury by focusing on topics such as delivery routes, regeneration efficacy, adverse effects, and in vivo potential optimization. PUBMED and Web of Science were searched for the latest studies examining stem cell therapy applications in ischemic brain injury, particularly after stroke or cardiac arrest, with a focus on studies addressing delivery optimization, stem cell type comparison, or translational aspects. Other studies providing further understanding or potential contributions to ischemic brain injury treatment were also included. Multiple stem cell types have been investigated in ischemic brain injury treatment, with a strong literature base in the treatment of stroke. Studies have suggested that stem cell administration after ischemic brain injury exerts paracrine effects via growth factor release, blood-brain barrier integrity protection, and allows for exosome release for ischemic injury mitigation. To date, limited studies have investigated these therapeutic mechanisms in the setting of cardiac arrest or therapeutic hypothermia. Several delivery modalities are available, each with limitations regarding invasiveness and safety outcomes. Intranasal delivery presents a potentially improved mechanism, and hypoxic conditioning offers a potential stem cell therapy optimization strategy for ischemic brain injury. The use of stem cells to treat ischemic brain injury in clinical trials is in its early phase; however, increasing preclinical evidence suggests that stem cells can contribute to the down-regulation of inflammatory phenotypes and regeneration following injury. The safety and the tolerability profile of stem cells have been confirmed, and their potent therapeutic effects make them powerful therapeutic agents for ischemic brain injury patients.

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