Jessica S. Wallisch

Background: Pediatric neurocritical care (PNCC) has emerged as a distinct field, and many hospitals have moved to establishing dedicated PNCC programs. How practice change is implemented within these programs is not well understood. This study had two objectives. First, we sought to understand the barriers and facilitators of practice change in PNCC from the perspectives of the multiprofessional clinicians who deliver it. Second, we sought to characterize how well the integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) implementation determinant framework captures them. Methods: We conducted semi-structured interviews with a purposive sample of clinicians involved in PNCC at three U.S. academic medical centers. The interview guide was developed using i-PARIHS to organize barriers and facilitators of practice change across the innovation, recipients, context, and facilitation constructs. We applied framework analysis, combining deductive i-PARIHS, study-specific, and inductively derived categories. Two coders independently indexed the transcripts and reconciled them to consensus, with first-author adjudication. Preliminary site-level findings were validated with participants. Results: We interviewed 33 clinicians: 24 physicians, 7 nurses, and 2 advanced practice providers. Most determinants of practice change mapped to existing i-PARIHS constructs, but three were not adequately captured by the framework as currently specified. The most consequential was an interprofessional authority gradient that determined whose preferences prevailed when intensive care, neurology, and neurosurgery disagreed. The other two were clinician autonomy, which served as the lens through which the acceptability of a change was judged, and the affective state clinicians bring to practice change. Receptivity depended more on recipients’ values, prior experience, and capacity to absorb change into a demanding workflow. Facilitation was variable, frequently under-resourced, and dependent on credibility across professional groups. We translated these findings into three propositions linked to implementation strategies and outcomes. Conclusions: Participants attributed practice change in PNCC more to the recipients of change, the multiprofessional context, and the availability of facilitation than to the strength of evidence for a given practice. i-PARIHS captured most barriers and facilitators well but may be adapted in this setting. Credible, resourced, authority-sensitive facilitation may improve the prospects for sustained practice change as institutions develop PNCC programs. Contributions to the literature: Determinant frameworks are widely used but rarely revised once published; this study supports three i-PARIHS framework modifications potentially applicable to the general pediatric ICU and PNCC programs regarding clinician autonomy, the affective state clinicians bring to change, and the interprofessional authority gradient. We identify authority-sensitive facilitation as an important driver of sustained practice change amongst multispecialty teams. We offer three i-PARIHS elaborations with linked implementation outcomes and implications for selecting implementation strategies for teams with shared authority across professions.

Background: Despite improving outcomes, extracorporeal membrane oxygenation (ECMO) remains associated with high rates of acute brain injury, impacting survival and outcomes. Clinical imaging modalities, including computed tomography and standard‐field magnetic resonance imaging (≥1.5 Tesla), have either limited early detection of ischemic‐type injuries or are incompatible with ECMO, causing diagnostic delays. A Food and Drug Administration–cleared ultra‐low‐field portable magnetic resonance imaging (pMRI; 0.064 Tesla) has shown promise in acute brain injury detection and use with MRI‐unsafe equipment, but pediatric ECMO data are limited. Methods: This institutional review board–approved, single‐center study was conducted at a quaternary children’s hospital. Neonatal and pediatric patients on ECMO from September 2023 to August 2024 were screened. Enrolled subjects underwent pMRI using Swoop (Hyperfine, Guilford, CT). Feasibility (resource use, concurrent equipment) and safety metrics (ECMO flow/vitals, cannula displacement) were collected along with patient/ECMO variables and all head imaging. Two blinded pediatric neuroradiologists independently reviewed images. Results: Of 41 screened patients, 20 were enrolled, 16 had pMRI attempted, and 11 completed full imaging (T1, T2, fluid‐attenuated inversion recovery, and diffusion‐weighted imaging). Median staff required for pMRI was 6 (interquartile range, 5–7) versus 7 (interquartile range, 7–7) for head computed tomography. Median pMRI positioning and imaging time was 66 (interquartile range, 61–70) minutes versus 75 (interquartile range, 70–79) minutes for head computed tomography with intrahospital transport. One subject had a ≥20% but clinically nonsignificant decrease in blood pressure; no safety events were attributable to pMRI. A total of 70% to 75% of image sets were of diagnostic quality. Conclusions: pMRI is feasible in pediatric ECMO with no clinically relevant complications, lower resource use, and generation of diagnostic quality images in our cohort. Registration Information: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT06074406.

Introduction Extracorporeal membrane oxygenation (ECMO) outcomes continue to improve, yet high rates of acute brain injury (ABI) threaten survival with significant morbidity for ECMO survivors. Currently available imaging modalities [ultrasound and computed tomography (CT)] have low early detection rates for hypoxic-ischemic and cerebrovascular injuries, delaying the diagnosis of ABI while on ECMO. CT sensitivity increases only when it may be too late to effectively intervene. High-field (>1.5 Tesla) magnetic resonance imaging (MRI), the gold standard to diagnose ischemic brain injury, is not compatible with ECMO. An FDA-cleared ultralow-field (0.064 Tesla) portable MRI (pMRI) has been studied in diverse types of ABI and with equipment that is typically not MRI compatible. There is very limited experience using pMRI in ECMO and even less in pediatric ECMO patients, therefore additional feasibility and safety data is needed in this cohort. Methods This single center, IRB approved study was conducted at a free-standing quaternary children’s hospital. All neonatal and pediatric patients cannulated onto ECMO were screened for eligibility. Subjects underwent bedside ultralow-field pMRI with Swoop (Hyperfine, Guilford, CT). Data on ECMO variables, time for patient positioning and scan, MRI sequences, concurrent critical care equipment, changes in ECMO flow and vital signs, and cannula displacement was collected. Results Over a 1-year period (Aug 2023-Aug 2024) 41 patients were screened. 16 out of 20 enrolled subjects had pMRI attempted and 13 (81.25%) received the full imaging protocol (T1, T2, FLAIR and DWI). The median staff members for pMRI positioning was 6 [5, 7] compared to 7 [7,7] for head CT (0.03). The median positioning and pMRI imaging time was 66 min [56, 70] compared to 75 min [70,79] for intrahospital transport for head CT. One subject had a ≥ 20% decrease in mean arterial pressure, however remained within the clinical goals without intervention. Unlike during head CT imaging acquisition, continuous renal replacement therapy was not interrupted during pMRI. Conclusions pMRI is safe and feasible in pediatric ECMO with no clinically relevant complications seen in our cohort. Resource utilization and delivery of concurrent critical care is superior for bedside imaging compared to intrahospital transport to CT. Clinical Trial Registration NCT06074406 https://clinicaltrials.gov/study/NCT06074406?term=NCT06074406Crank=1 What is new? This study expands the experience of ultralow-field portable MRI to pediatric ECMO patients. Ultralow-field portable MRI is feasible and less resource-intense to perform on pediatric ECMO patients compared to intrahospital transport for head CT. Pediatric ECMO patients tolerate bedside MRI without clinically significant changes in ECMO flows, perfusion, or oxygenation. What are the clinical implications? Ultralow-field portable MRI can expand time-sensitive head imaging options for pediatric patients on ECMO with less interruptions of critical care therapies, decreased resource utilization, and eliminated risks of travel and radiation exposure. Timely diagnosis of acute brain injury while on ECMO can prompt changes in neuromonitoring, anticoagulation management, and delivery of neuroprotective care with the intent to improve neurologic outcomes of pediatric ECMO survivors.

Background: Pediatric oncology patients with sepsis are at higher risk of morbidity and mortality compared with pediatric patients without malignancy. Historically, patients with relapsed and/or refractory disease were not considered candidates for aggressive life support strategies including extracorporeal membrane oxygenation support. Case Summary: We report a 4-year-old female with relapsed refractory pre-B cell acute lymphoblastic leukemia preparing for chimeric antigen receptor T cell therapy with tisagenlecleucel who was admitted with fever and neutropenia. She progressed to refractory septic shock secondary to Escherichia coli bacteremia and required escalation of hemodynamic support to venoarterial extracorporeal membrane oxygenation cannulation. She cleared her E. coli bacteremia, was decannulated, subsequently received her chimeric antigen receptor T-cell therapy, and was declared disease free 1 month from her initial presentation. Conclusion: The ability to provide chimeric antigen receptor T-cell therapy at designated institutions can augment extracorporeal membrane oxygenation candidacy discussions in oncology patients with relapsed disease and may make extracorporeal membrane oxygenation candidacy for oncology patients with refractory sepsis more favorable.

Objectives: Intracranial pressure in traumatic brain injury is dynamic and influenced by factors like injury patterns, treatments, and genetics. Existing studies use time invariant summary intracranial pressure measures thus potentially losing critical information about temporal trends. We identified longitudinal intracranial pressure trajectories in severe traumatic brain injury and evaluated whether they predicted outcome. We further interrogated the model to explore whetherABCC8polymorphisms (a known cerebraledema regulator) differed across trajectory groups.Design: Prospective observational cohort.Setting: Single-center academic medical center.Patients: Four-hundred four severe traumatic brain injury patients.Interventions: None.Measurements and Main Results: We used group-based trajectory modeling to identify hourly intracranial pressure trajectories in days 0–5 post traumatic brain injury incorporating risk factor adjustment (age, sex, Glasgow Coma Scale 6score, craniectomy, primary hemorrhage pattern). We compared 6-month outcomes (Glasgow Outcome Scale, Disability Rating Scale, mortality) andABCC8tag-single-nucleotide polymorphisms associated with cerebral edema (rs2237982, rs7105832) across groups. Regression models determined whether trajectory groups predicted outcome. A six trajectory group model best fit the data, identifying cohorts differing in initial intracranial pressure, evolution, and number/proportion of spikes greater than 20 mm Hg. There were pattern differences in age, hemorrhage type, and craniectomy rates.ABCC8polymorphisms differed across groups. GOS (p= 0.006), Disability Rating Scale (p= 0.001), mortality (p< 0.0001), and rs2237982 (p= 0.035) differed across groups. Unfavorable outcomes were surprisingly predicted by both low intracranial pressure trajectories and sustained intracranial hypertension. Intracranial pressure variability differed across groups (p< 0.001) and may reflect preserved/impaired intracranial elastance/compliance.Conclusions: We employed a novel approach investigating longitudinal/dynamic intracranial pressure patterns in traumatic brain injury. In a risk adjusted model, six groups were identified and predicted outcomes. If validated, trajectory modeling may be a first step toward developing a new, granular approach for intracranial pressure phenotyping in conjunction with other phenotyping tools like biomarkers and neuroimaging. This may be particularly relevant in light of changing traumatic brain injury demographics toward the elderly.

Background Cerebral edema after cardiac arrest (CA) is associated with increased mortality and unfavorable outcome in children and adults. Aquaporin-4 mediates cerebral water movement and its absence in models of ischemia improves outcome. We investigated early and selective pharmacologic inhibition of aquaporin-4 in a clinically relevant asphyxial CA model in immature rats in a threshold CA insult that produces primarily cytotoxic edema in the absence of blood-brain barrier permeability. Methods Postnatal day 16–18 Sprague-Dawley rats were studied in our established 9-min asphyxial CA model. Rats were randomized to aquaporin-4 inhibitor (AER-271) vs vehicle treatment, initiated at return of spontaneous circulation. Cerebral edema (% brain water) was the primary outcome with secondary assessments of the Neurologic Deficit Score (NDS), hippocampal neuronal death, and neuroinflammation. Results Treatment with AER-271 ameliorated early cerebral edema measured at 3 h after CA vs vehicle treated rats. This treatment also attenuated early NDS. In contrast to rats treated with vehicle after CA, rats treated with AER-271 did not develop significant neuronal death or neuroinflammation as compared to sham. Conclusion Early post-resuscitation aquaporin-4 inhibition blocks the development of early cerebral edema, reduces early neurologic deficit, and blunts neuronal death and neuroinflammation post-CA.

Cerebral edema is critical to morbidity/mortality in traumatic brain injury (TBI) and is worsened by hypotension. Glibenclamide may reduce cerebral edema by inhibiting sulfonylurea receptor-1 (Sur1); its effect on diffuse cerebral edema exacerbated by hypotension/resuscitation is unknown. We aimed to determine if glibenclamide improves pericontusional and/or diffuse edema in controlled cortical impact (CCI) (5m/sec, 1 mm depth) plus hemorrhagic shock (HS) (35 min), and compare its effects in CCI alone. C57BL/6 mice were divided into five groups (n = 10/group): naïve, CCI+vehicle, CCI+glibenclamide, CCI+HS+vehicle, and CCI+HS+glibenclamide. Intravenous glibenclamide (10 min post-injury) was followed by a subcutaneous infusion for 24 h. Brain edema in injured and contralateral hemispheres was subsequently quantified (wet-dry weight). This protocol brain water (BW) = 80.4% vehicle vs. 78.3% naïve, p < 0.01) but was not reduced by glibenclamide (I%BW = 80.4%). Ipsilateral edema also developed in CCI alone (I%BW = 80.2% vehicle vs. 78.3% naïve, p < 0.01); again unaffected by glibenclamide (I%BW = 80.5%). Contralateral (C) %BW in CCI+HS was increased in vehicle (78.6%) versus naive (78.3%, p = 0.02) but unchanged in CCI (78.3%). At 24 h, glibenclamide treatment in CCI+HS eliminated contralateral cerebral edema (C%BW = 78.3%) with no difference versus naïve. By 72 h, contralateral cerebral edema had resolved (C%BW = 78.5 ± 0.09% vehicle vs. 78.3 ± 0.05% naïve). Glibenclamide decreased 24 h contralateral cerebral edema in CCI+HS. This beneficial effect merits additional exploration in the important setting of TBI with polytrauma, shock, and resuscitation. Contralateral edema did not develop in CCI alone. Surprisingly, 24 h of glibenclamide treatment failed to decrease ipsilateral edema in either model. Interspecies dosing differences versus prior studies may play an important role in these findings. Mechanisms underlying brain edema may differ regionally, with pericontusional/osmolar swelling refractory to glibenclamide but diffuse edema (via Sur1) from combined injury and/or resuscitation responsive to this therapy. TBI phenotype may mandate precision medicine approaches to treat brain edema.

Objective: ABCC8 encodes sulfonylurea receptor 1, a key regulatory protein of cerebral oedema in many neurological disorders including traumatic brain injury (TBI). Sulfonylurea-receptor-1 inhibition has been promising in ameliorating cerebral oedema in clinical trials. We evaluated whether ABCC8 tag single-nucleotide polymorphisms predicted oedema and outcome in TBI.Methods: DNA was extracted from 485 prospectively enrolled patients with severe TBI. 410 were analysed after quality control. ABCC8 tag single-nucleotide polymorphisms (SNPs) were identified (Hapmap, r²>0.8, minor-allele frequency >0.20) and sequenced (iPlex-Gold, MassArray). Outcomes included radiographic oedema, intracranial pressure (ICP) and 3-month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modelling, amino acid topology and functional predictions were determined using established software programs.Results: Wild-type rs7105832 and rs2237982 alleles and genotypes were associated with lower average ICP (β=−2.91, p=0.001; β=−2.28, p=0.003) and decreased radiographic oedema (OR 0.42, p=0.012; OR 0.52, p=0.017). Wild-type rs2237982 also increased favourable 3-month GOS (OR 2.45, p=0.006); this was partially mediated by oedema (p=0.03). Different polymorphisms predicted 3-month outcome: variant rs11024286 increased (OR 1.84, p=0.006) and wild-type rs4148622 decreased (OR 0.40, p=0.01) the odds of favourable outcome. Significant tag and concordant proxy SNPs regionally span introns/exons 2–15 of the 39-exon gene.Conclusions: This study identifies four ABCC8 tag SNPs associated with cerebral oedema and/or outcome in TBI, tagging a region including 33 polymorphisms. In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk. Different variant polymorphisms were associated with favourable outcome, potentially suggesting distinct mechanisms. Significant polymorphisms spatially clustered flanking exons encoding the sulfonylurea receptor site and transmembrane domain 0/loop 0 (juxtaposing the channel pore/binding site). This, if validated, may help build a foundation for developing future strategies that may guide individualised care, treatment response, prognosis and patient selection for clinical trials.

Purpose Despite the enormity of the problem and the lack of new therapies, research in the pre-clinical arena specifically using pediatric traumatic brain injury (TBI) models is limited. In this review, some of the key models addressing both the age spectrum of pediatric TBI and its unique injury mechanisms will be highlighted. Four topics will be addressed, namely, (1) unique facets of the developing brain important to TBI model development, (2) a description of some of the most commonly used pre-clinical models of severe pediatric TBI including work in both rodents and large animals, (3) a description of the pediatric models of mild TBI and repetitive mild TBI that are relatively new, and finally (4) a discussion of challenges, gaps, and potential future directions to further advance work in pediatric TBI models. Methods This narrative review on the topic of pediatric TBI models was based on review of PUBMED/Medline along with a synthesis of information on key factors in pre-clinical and clinical developmental brain injury that influence TBI modeling. Results In the contemporary literature, six types of models have been used in rats including weight drop, fluid percussion injury (FPI), impact acceleration, controlled cortical impact (CCI), mechanical shaking, and closed head modifications of CCI. In mice, studies are largely restricted to CCI. In large animals, FPI and rotational injury have been used in piglets and shake injury has also been used in lambs. Most of the studies have been in severe injury models, although more recently, studies have begun to explore mild and repetitive mild injuries to study concussion. Conclusions Given the emerging importance of TBI in infants and children, the morbidity and mortality that is produced, along with its purported link to the development of chronic neurodegenerative diseases, studies in these models merit greater systematic investigations along with consortium-type approaches and long-term follow-up to translate new therapies to the bedside.