Association of blood-based brain injury biomarker concentrations with outcomes after pediatric cardiac arrest

Importance: Families and clinicians have limited validated tools available to assist in estimating long-term outcomes early after pediatric cardiac arrest. Blood-based brain-specific biomarkers may be helpful tools to aid in outcome assessment. Objective: To analyze the association of blood-based brain injury biomarker concentrations with outcomes 1 year after pediatric cardiac arrest. Design, Setting, and Participants: The Personalizing Outcomes After Child Cardiac Arrest multicenter prospective cohort study was conducted in pediatric intensive care units at 14 academic referral centers in the US between May 16, 2017, and August 19, 2020, with the primary investigators blinded to 1-year outcomes. The study included 120 children aged 48 hours to 17 years who were resuscitated after cardiac arrest, had pre-cardiac arrest Pediatric Cerebral Performance Category scores of 1 to 3 points, and were admitted to an intensive care unit after cardiac arrest. Exposure: Cardiac arrest. Main Outcomes and Measures: The primary outcome was an unfavorable outcome (death or survival with a Vineland Adaptive Behavior Scales, third edition, score of \u3c70 points) at 1 year after cardiac arrest. Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal esterase L1 (UCH-L1), neurofilament light (NfL), and tau concentrations were measured in blood samples from days 1 to 3 after cardiac arrest. Multivariate logistic regression and area under the receiver operating characteristic curve (AUROC) analyses were performed to examine the association of each biomarker with outcomes on days 1 to 3. Results: Among 120 children with primary outcome data available, the median (IQR) age was 1.0 (0-8.5) year; 71 children (59.2%) were male. A total of 5 children (4.2%) were Asian, 19 (15.8%) were Black, 81 (67.5%) were White, and 15 (12.5%) were of unknown race; among 110 children with data on ethnicity, 11 (10.0%) were Hispanic, and 99 (90.0%) were non-Hispanic. Overall, 70 children (58.3%) had a favorable outcome, and 50 children (41.7%) had an unfavorable outcome, including 43 deaths. On days 1 to 3 after cardiac arrest, concentrations of all 4 measured biomarkers were higher in children with an unfavorable vs a favorable outcome at 1 year. After covariate adjustment, NfL concentrations on day 1 (adjusted odds ratio [aOR], 5.91; 95% CI, 1.82-19.19), day 2 (aOR, 11.88; 95% CI, 3.82-36.92), and day 3 (aOR, 10.22; 95% CI, 3.14-33.33); UCH-L1 concentrations on day 2 (aOR, 11.27; 95% CI, 3.00-42.36) and day 3 (aOR, 7.56; 95% CI, 2.11-27.09); GFAP concentrations on day 2 (aOR, 2.31; 95% CI, 1.19-4.48) and day 3 (aOR, 2.19; 95% CI, 1.19-4.03); and tau concentrations on day 1 (aOR, 2.44; 95% CI, 1.14-5.25), day 2 (aOR, 2.28; 95% CI, 1.31-3.97), and day 3 (aOR, 2.04; 95% CI, 1.16-3.57) were associated with an unfavorable outcome. The AUROC models were significantly higher with vs without the addition of NfL on day 2 (AUROC, 0.932 [95% CI, 0.877-0.987] vs 0.871 [95% CI, 0.793-0.949]; P = .02) and day 3 (AUROC, 0.921 [95% CI, 0.857-0.986] vs 0.870 [95% CI, 0.786-0.953]; P = .03). Conclusions and Relevance: In this cohort study, blood-based brain injury biomarkers, especially NfL, were associated with an unfavorable outcome at 1 year after pediatric cardiac arrest. Additional evaluation of the accuracy of the association between biomarkers and neurodevelopmental outcomes beyond 1 year is needed

Assessment of brain magnetic resonance and spectroscopy imaging findings and outcomes after pediatric cardiac arrest

IMPORTANCE: Morbidity and mortality after pediatric cardiac arrest are chiefly due to hypoxic-ischemic brain injury. Brain features seen on magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) after arrest may identify injury and aid in outcome assessments. OBJECTIVE: To analyze the association of brain lesions seen on T2-weighted MRI and diffusion-weighted imaging and N-acetylaspartate (NAA) and lactate concentrations seen on MRS with 1-year outcomes after pediatric cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study took place in pediatric intensive care units at 14 US hospitals between May 16, 2017, and August 19, 2020. Children aged 48 hours to 17 years who were resuscitated from in-hospital or out-of-hospital cardiac arrest and who had a clinical brain MRI or MRS performed within 14 days postarrest were included in the study. Data were analyzed from January 2022 to February 2023. EXPOSURE: Brain MRI or MRS. MAIN OUTCOMES AND MEASURES: The primary outcome was an unfavorable outcome (either death or survival with a Vineland Adaptive Behavior Scales, Third Edition, score of \u3c70) at 1 year after cardiac arrest. MRI brain lesions were scored according to region and severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) by 2 blinded pediatric neuroradiologists. MRI Injury Score was a sum of T2-weighted and diffusion-weighted imaging lesions in gray and white matter (maximum score, 34). MRS lactate and NAA concentrations in the basal ganglia, thalamus, and occipital-parietal white and gray matter were quantified. Logistic regression was performed to determine the association of MRI and MRS features with patient outcomes. RESULTS: A total of 98 children, including 66 children who underwent brain MRI (median [IQR] age, 1.0 [0.0-3.0] years; 28 girls [42.4%]; 46 White children [69.7%]) and 32 children who underwent brain MRS (median [IQR] age, 1.0 [0.0-9.5] years; 13 girls [40.6%]; 21 White children [65.6%]) were included in the study. In the MRI group, 23 children (34.8%) had an unfavorable outcome, and in the MRS group, 12 children (37.5%) had an unfavorable outcome. MRI Injury Scores were higher among children with an unfavorable outcome (median [IQR] score, 22 [7-32]) than children with a favorable outcome (median [IQR] score, 1 [0-8]). Increased lactate and decreased NAA in all 4 regions of interest were associated with an unfavorable outcome. In a multivariable logistic regression adjusted for clinical characteristics, increased MRI Injury Score (odds ratio, 1.12; 95% CI, 1.04-1.20) was associated with an unfavorable outcome. CONCLUSIONS AND RELEVANCE: In this cohort study of children with cardiac arrest, brain features seen on MRI and MRS performed within 2 weeks after arrest were associated with 1-year outcomes, suggesting the utility of these imaging modalities to identify injury and assess outcomes

Decompressive craniectomy reduces white matter injury after controlled cortical impact in mice

Reduction and avoidance of increases in intracranial pressure (ICP) after severe traumatic brain injury (TBI) continue to be the mainstays of treatment. Traumatic axonal injury is a major contributor to morbidity after TBI, but it remains unclear whether elevations in ICP influence axonal injury. Here we tested the hypothesis that reduction in elevations in ICP after experimental TBI would result in decreased axonal injury and white matter atrophy in mice. Six-week-old male mice (C57BL/6J) underwent either moderate controlled cortical impact (CCI) (n=48) or Sham surgery (Sham, n=12). Immediately after CCI, injured animals were randomized to a loose fitting plastic cap (Open) or replacement of the previously removed bone flap (Closed). Elevated ICP was observed in Closed animals compared with Open and Sham at 15 min (21.4±4.2 vs. 12.3±2.9 and 8.8±1.8 mm Hg, p<0.0001) and 1 day (17.8±3.7 vs. 10.6±2.0 and 8.9±1.9 mm Hg, p<0.0001) after injury. Beta amyloid precursor protein staining in the corpus callosum and ipsilateral external capsule revealed reduced axonal swellings and bulbs in Open compared with Closed animals (32% decrease, p<0.01 and 40% decrease, p<0.001 at 1 and 7 days post-injury, respectively). Open animals were also found to have decreased neurofilament-200 stained axonal swellings at 7 days post-injury compared with Open animals (32% decrease, p<0.001). At 4 weeks post-injury, Open animals had an 18% reduction in white matter volume compared with 34% in Closed animals (p<0.01). Thus, our results indicate that CCI with decompressive craniectomy was associated with reductions in ICP and reduced pericontusional axonal injury and white matter atrophy. If similar in humans, therapeutic interventions that ameliorate intracranial hypertension may positively influence white matter injury severity

Advanced Neuromonitoring and Imaging in Pediatric Traumatic Brain Injury

While the cornerstone of monitoring following severe pediatric traumatic brain injury is serial neurologic examinations, vital signs, and intracranial pressure monitoring, additional techniques may provide useful insight into early detection of evolving brain injury. This paper provides an overview of recent advances in neuromonitoring, neuroimaging, and biomarker analysis of pediatric patients following traumatic brain injury

Identification of post-cardiac arrest blood pressure thresholds associated with outcomes in children: An ICU-Resuscitation study

INTRODUCTION: Though early hypotension after pediatric in-hospital cardiac arrest (IHCA) is associated with inferior outcomes, ideal post-arrest blood pressure (BP) targets have not been established. We aimed to leverage prospectively collected BP data to explore the association of post-arrest BP thresholds with outcomes. We hypothesized that post-arrest systolic and diastolic BP thresholds would be higher than the currently recommended post-cardiopulmonary resuscitation BP targets and would be associated with higher rates of survival to hospital discharge. METHODS: We performed a secondary analysis of prospectively collected BP data from the first 24 h following return of circulation from index IHCA events enrolled in the ICU-RESUScitation trial (NCT02837497). The lowest documented systolic BP (SBP) and diastolic BP (DBP) were percentile-adjusted for age, height and sex. Receiver operator characteristic curves and cubic spline analyses controlling for illness category and presence of pre-arrest hypotension were generated exploring the association of lowest post-arrest SBP and DBP with survival to hospital discharge and survival to hospital discharge with favorable neurologic outcome (Pediatric Cerebral Performance Category of 1-3 or no change from baseline). Optimal cutoffs for post-arrest BP thresholds were based on analysis of receiver operator characteristic curves and spline curves. Logistic regression models accounting for illness category and pre-arrest hypotension examined the associations of these thresholds with outcomes. RESULTS: Among 693 index events with 0-6 h post-arrest BP data, identified thresholds were: SBP \u3e 10th percentile and DBP \u3e 50th percentile for age, sex and height. Fifty-one percent (n = 352) of subjects had lowest SBP above threshold and 50% (n = 346) had lowest DBP above threshold. SBP and DBP above thresholds were each associated with survival to hospital discharge (SBP: aRR 1.21 [95% CI 1.10, 1.33]; DBP: aRR 1.23 [1.12, 1.34]) and survival to hospital discharge with favorable neurologic outcome (SBP: aRR 1.22 [1.10, 1.35]; DBP: aRR 1.27 [1.15, 1.40]) (all p \u3c 0.001). CONCLUSIONS: Following pediatric IHCA, subjects had higher rates of survival to hospital discharge and survival to hospital discharge with favorable neurologic outcome when BP targets above a threshold of SBP \u3e 10th percentile for age and DBP \u3e 50th percentile for age during the first 6 h post-arrest

The Anesthetic Effects on Vasopressor Modulation of Cerebral Blood Flow in an Immature Swine Model

BACKGROUND: The effect of various sedatives and anesthetics on vasopressor modulation of cerebral blood flow (CBF) in children is unclear. In adults, isoflurane has been described to decrease CBF to a lesser extent than fentanyl and midazolam. Most large-animal models of neurocritical care use inhaled anesthetics for anesthesia. Investigations involving modulations of CBF would have improved translatability within a model that more closely approximates the current practice in the pediatric intensive care unit. METHODS: Fifteen 4-week-old piglets were given 1 of 2 anesthetic protocols: total IV anesthesia (TIVA) (midazolam 1 mg/kg/h and fentanyl 100 μg/kg/h, n = 8) or ISO (isoflurane 1.5%–2% and fentanyl 100 μg/kg/h, n = 7). Mean arterial blood pressure, intracranial pressure (ICP), CBF, and brain tissue oxygen tension were measured continuously as piglets were exposed to escalating doses of arginine vasopressin, norepinephrine (NE), and phenylephrine (PE). RESULTS: Baseline CBF was similar in the 2 groups (ISO 38 ± 10 vs TIVA 35 ± 26 mL/100 g/min) despite lower baseline cerebral perfusion pressure in the ISO group (45 ± 11 vs 71 ± 11 mm Hg; P \u3c 0.0005). Piglets in the ISO group displayed increases in ICP with PE and NE (11 ± 4 vs 16 ± 4 mm Hg and 11 ± 8 vs 18 ± 5 mm Hg; P \u3c 0.05), but in the TIVA group, only exposure to PE resulted in increases in ICP when comparing maximal dose values with baseline data (11 ± 4 vs 15 ± 5 mm Hg; P \u3c 0.05). Normalized CBF displayed statistically significant increases regarding anesthetic group and vasopressor dose when piglets were exposed to NE and PE (P \u3c 0.05), suggesting an impairment of autoregulation within ISO, but not TIVA. CONCLUSION: The vasopressor effect on CBF was limited when using a narcotic-benzodiazepine–based anesthetic protocol compared with volatile anesthetics, consistent with a preservation of autoregulation. Selection of anesthetic drugs is critical to investigate mechanisms of cerebrovascular hemodynamics, and in translating critical care investigations between the laboratory and bedside

Behavioral Deficits and Axonal Injury Persistence after Rotational Head Injury Are Direction Dependent

Pigs continue to grow in importance as a tool in neuroscience. However, behavioral tests that have been validated in the rodent model do not translate well to pigs because of their very different responses to behavioral stimuli. We refined metrics for assessing porcine open field behavior to detect a wide spectrum of clinically relevant behaviors in the piglet post-traumatic brain injury (TBI). Female neonatal piglets underwent a rapid non-impact head rotation in the sagittal plane (n=8 evaluable) or were instrumented shams (n=7 evaluable). Open field testing was conducted 1 day prior to injury (day −1) in order to establish an individual baseline for analysis, and at days +1 and +4 after injury. Animals were then killed on day +6 after injury for neuropathological assessment of axonal injury. Injured piglets were less interested in interacting with environmental stimuli and had a lower activity level than did shams. These data were compared with previously published data for axial rotational injuries in neonatal piglets. Acute behavioral outcomes post-TBI showed a dependence on the rotational plane of the brain injury, with animals with sagittal injuries demonstrating a greater level of inactivity and less random usage of the open field space than those with axial injuries. The persistence of axonal injury is also dependent on the rotational plane, with sagittal rotations causing more prolonged injuries than axial rotations. These results are consistent with animal studies, finite element models, and studies of concussions in football, which have all demonstrated differences in injury severity depending upon the direction of head impact rotation

Differing effects when using phenylephrine and norepinephrine to augment cerebral blood flow after traumatic brain injury in the immature brain

Low cerebral blood flow (CBF) states have been demonstrated in children early after traumatic brain injury (TBI), and have been correlated with poorer outcomes. Cerebral perfusion pressure (CPP) support following severe TBI is commonly implemented to correct cerebral hypoperfusion, but the efficacy of various vasopressors has not been determined. Sixteen 4-week-old female swine underwent nonimpact inertial brain injury in the sagittal plane. Intraparenchymal monitors were placed to measure intracranial pressure (ICP), CBF, brain tissue oxygen tension (PbtO(2)), and cerebral microdialysis 30 min to 6 h post-injury. One hour after injury, animals were randomized to receive either phenylephrine (PE) or norepinephrine (NE) infusions titrated to a CPP >70 mm Hg for 5 h. Animals were euthanized 6 h post-TBI, and brains were fixed and stained to assess regions of cell and axonal injury. After initiation of CPP augmentation with NE or PE infusions, there were no differences in ICP between the groups or over time. Animals receiving NE had higher PbtO(2) than those receiving PE (29.6±10.2 vs. 19.6±6.4 torr at 6 h post-injury, p<0.05). CBF increased similarly in both the NE and PE groups. CPP support with PE resulted in a greater reduction in metabolic crisis than with NE (lactate/pyruvate ratio 16.7±2.4 vs. 42.7±10.2 at 6 h post-injury, p<0.05). Augmentation of CPP to 70 mm Hg with PE resulted in significantly smaller cell injury volumes at 6 h post-injury than CPP support with NE (0.4% vs. 1.4%, p<0.05). Despite similar increases in CBF, CPP support with NE resulted in greater brain tissue oxygenation and hypoxic-ischemic injury than CPP support with PE. Future clinical studies comparing the effectiveness of various vasopressors for CPP support are warranted

Premedication With Meloxicam Exacerbates Intracranial Hemorrhage in an Immature Swine Model of Non-impact Inertial Head Injury

Meloxicam is a cyclo-oxgenase-2 preferential non-steroid anti-inflammatory drug with very effective analgesic and anti-inflammatory effects in swine. Previous reports in piglets have demonstrated that meloxicam also inhibits cyclo-oxgenase-1 and reduces production of thromboxane significantly. We use pre-injury analgesia in our immature swine (3–5 day old piglets) model of brain injury using rapid head rotations without impact. In 23 consecutive subjects we found that premedication with meloxicam (N=6) produced a significantly higher mortality rate (5/6 or 83%) than buprenorphine (N =17, 1/17 or 6%, p \u3c 0.02). On gross neuropathologic examination of the meloxicam-treated swine, we observed massive subdural and subarachnoid bleeding which were not present in buprenorphine-premedicated animals. To our knowledge there are no previous reports in swine of increased bleeding or platelet inhibition associated with meloxicam administration and further research is needed to define mechanisms of action in piglets. We caution the use of meloxicam in swine when inhibition of platelet aggregation might adversely affect refinement of experimental research protocols, such as in stroke, trauma, and cardiac arrest models