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OBJECTIVES To describe rehabilitation practice patterns among critically ill children with prolonged ICU stays and explore the association between institution-level utilization of rehabilitative services and patient outcomes. DESIGN Retrospective cohort study using an administrative database of inpatient clinical and resource utilization data from participating pediatric hospitals in the United States. Center-level utilization of physical therapy and occupational therapy among critically ill patients was used to divide hospitals by quartile into high utilization centers or standard utilization centers. SETTING Fifty-one pediatric hospitals in the United States. PATIENTS Critically ill pediatric patients with prolonged critical illness (defined as an ICU length of stay of at least 7 d) discharged from July 2016 to June 2017. INTERVENTIONS Not applicable. MEASUREMENTS AND MAIN RESULTS Seventeen thousand four hundred seventy encounters met criteria for study inclusion. Of those, 6,040 (35%) were not charged for either physical therapy or occupational therapy services. There was wide variability in center-level utilization of rehabilitative services while in the ICU, ranging from 81% utilization of physical therapy or occupational therapy services among high utilization centers to 46% utilization among centers within the lowest quartile. In univariate analyses, children cared for at an high utilization center were less likely to require discharge to an inpatient rehabilitation facility (1.7% vs 3.5%; p < 0.001) and less likely to incur a new pressure injury (2.2% vs 3.1%; p = 0.001). In multivariable analyses, the direction and magnitude of effects remained similar, although the effect was no longer statistically significant (discharge to inpatient rehabilitation facility: odds ratio, 0.64; 95% CI, 0.18-2.26; pressure injury: odds ratio, 0.77; 95% CI, 0.48-1.24). CONCLUSIONS Institutional use of rehabilitative services for children with prolonged critical illness varies greatly in the United States. Further research is needed into the potential benefits for patients cared for at centers with high usage of rehabilitation services in the ICU during prolonged critical illness.

Diversion of cerebrospinal fluid (CSF) has been used for decades as a treatment for children with severe traumatic brain injury (TBI) and is recommended by evidenced-based guidelines. However, these recommendations are based on limited studies.To determine whether CSF diversion is associated with improved Glasgow Outcome Score-Extended for Pediatrics (GOS-EP) and decreased intracranial pressure (ICP) in children with severe TBI.This observational comparative effectiveness study was performed at 51 clinical centers that routinely care for children with severe TBI in 8 countries (US, United Kingdom, Spain, the Netherlands, Australia, New Zealand, South Africa, and India) from February 2014 to September 2017, with follow-up at 6 months after injury (final follow-up, October 22, 2021). Children with severe TBI were included if they had Glasgow Coma Scale (GCS) scores of 8 or lower, had intracranial pressure (ICP) monitor placed on-site, and were aged younger than 18 years. Children were excluded if they were pregnant or an ICP monitor was not placed at the study site. Consecutive children were screened and enrolled, data regarding treatments were collected, and at discharge, consent was obtained for outcomes testing. Propensity matching for pretreatment characteristics was performed to develop matched pairs for primary analysis. Data analyses were completed on April 18, 2022.Clinical care followed local standards, including the use of CSF diversion (or not), with patients stratified at the time of ICP monitor placement (CSF group vs no CSF group).The primary outcome was GOS-EP at 6 months, while ICP was considered as a secondary outcome. CSF vs no CSF was treated as an intention-to-treat analysis, and a sensitivity analysis was performed for children who received delayed CSF diversion.A total of 1000 children with TBI were enrolled, including 314 who received CSF diversion (mean [SD] age, 7.18 [5.45] years; 208 [66.2%] boys) and 686 who did not (mean [SD] age, 7.79 [5.33] years; 437 [63.7%] boys). The propensity-matched analysis included 98 pairs. In propensity score-matched analyses, there was no difference between groups in GOS-EP (median [IQR] difference, 0 [-3 to 1]; P = .08), but there was a decrease in overall ICP in the CSF group (mean [SD] difference, 3.97 [0.12] mm Hg; P .001).In this comparative effectiveness study, CSF diversion was not associated with improved outcome at 6 months after TBI, but a decrease in ICP was observed. Given the higher quality of evidence generated by this study, current evidence-based guidelines related to CSF diversion should be reconsidered.

With decreasing mortality in PICUs, a growing number of survivors experience long-lasting physical impairments. Early physical rehabilitation and mobilization during critical illness are safe and feasible, but little is known about the prevalence in PICUs. We aimed to evaluate the prevalence of rehabilitation for critically ill children and associated barriers.National 2-day point prevalence study.Eighty-two PICUs in 65 hospitals across the United States.All patients admitted to a participating PICU for greater than or equal to 72 hours on each point prevalence day.None.The primary outcome was prevalence of physical therapy- or occupational therapy-provided mobility on the study days. PICUs also prospectively collected timing of initial rehabilitation team consultation, clinical and patient mobility data, potential mobility-associated safety events, and barriers to mobility. The point prevalence of physical therapy- or occupational therapy-provided mobility during 1,769 patient-days was 35% and associated with older age (adjusted odds ratio for 13-17 vs3 yr, 2.1; 95% CI, 1.5-3.1) and male gender (adjusted odds ratio for females, 0.76; 95% CI, 0.61-0.95). Patients with higher baseline function (Pediatric Cerebral Performance Category, ≤ 2 vs2) less often had rehabilitation consultation within the first 72 hours (27% vs 38%; p0.001). Patients were completely immobile on 19% of patient-days. A potential safety event occurred in only 4% of 4,700 mobility sessions, most commonly a transient change in vital signs. Out-of-bed mobility was negatively associated with the presence of an endotracheal tube (adjusted odds ratio, 0.13; 95% CI, 0.1-0.2) and urinary catheter (adjusted odds ratio, 0.28; 95% CI, 0.1-0.6). Positive associations included family presence in children less than 3 years old (adjusted odds ratio, 4.55; 95% CI, 3.1-6.6).Younger children, females, and patients with higher baseline function less commonly receive rehabilitation in U.S. PICUs, and early rehabilitation consultation is infrequent. These findings highlight the need for systematic design of rehabilitation interventions for all critically ill children at risk of functional impairments.

Background Pediatric stroke alerts or “code strokes” allow for rapid evaluation, imaging, and treatment of children presenting with stroke-like symptoms. In a previous study of emergency department-initiated pediatric stroke alerts, 24% of children had confirmed strokes. The purpose of this study was to characterize in-hospital pediatric stroke alerts. Methods Demographic and clinical information was obtained from a quality improvement database and medical records for children (zero to 20 years) at a single institution for whom a stroke alert was activated after hospital admission between April 2011 and December 2016. Stroke alert activation criteria included a new focal neurological defect occurring within 48 hours. A neurologist evaluated the patient within 15 minutes and rapid magnetic resonance imaging was available. Results Medical personnel activated in-hospital stroke alerts for 56 children (median age 6.5 years, interquartile range 1 to 13, 52% male). Stroke was the final diagnosis of 25 (45%), 72% ischemic, and 28% hemorrhagic strokes. Other diagnoses included neurological urgencies: seizure (21%), posterior reversible encephalopathy syndrome (7%), transient ischemic attack (5%), and acute disseminated encephalomyelitis (4%). Of the stroke diagnoses, 68% were stroke alerts called in the pediatric intensive care unit or pediatric cardiac intensive care unit. Rapid neuroimaging was completed in 91%; magnetic resonance imaging brain was the first image in 55%. Conclusions Of in-hospital pediatric stroke alerts, 45% were stroke while 38% were other neurological conditions requiring urgent evaluation. In-hospital stroke alerts were commonly activated for children with complicated medical histories. Rapid neurological evaluation facilitated care. No child underwent thrombolysis or thrombectomy.

In traumatic brain injury (TBI), hyperglycemia and hypothermia are thought to be associated with poor outcomes, but have not been systematically studied in children. Thus, our aim was to evaluate whether serum glucose and temperature at admission, among other clinical variables, were associated with need for post hospital-discharge seizure medication in children diagnosed with TBI.We performed a retrospective study of 1814 children who were diagnosed with TBI at a tertiary pediatric hospital. Serum glucose levels at admission and temperature at initial presentation, 12, and 24 h were collected. Ongoing seizure activity was defined as discharge prescription of a seizure-modifying medication.We identified 121 patients with need for continued seizure medications, and 80 patients expired. Independent predictors of prolonged seizures included serum glucose levels above 140 mg/dl (p 0.003) and 199 mg/dl (p 0.001), hypothermia (35 °C), subdural hematoma (p 0.001), midline shift (p 0.001), and 1% temperature change in the first 24 h (p 0.001). Multivariate regression adjusting for GCS revealed that bilateral bleed (p = 0.008), body-temperature instability (p = 0.026), subdural hematoma (p 0.001), and mechanism of injury (p = 0.007) were predictive of prolonged seizure activity.In summary, we conclude that body temperature may be playing a more significant role than glycemic control in propensity for ongoing seizure activity in children sustaining TBI.

Neurologic complications can occur with extracorporeal membrane oxygenation (ECMO) due to several factors. Prior studies identified neonates as having unique risk factors and neuroimaging findings post ECMO. The aim of this study is to describe brain magnetic resonance imaging findings of pediatric patients treated with ECMO. We conducted a retrospective study of nonneonatal pediatric patients who underwent a comprehensive brain magnetic resonance imaging after ECMO between January 2000 and July 2015. We identified 47 pediatric patients in the study cohort with a median age of 8 months (interquartile range 3-170 months) and a median ECMO run duration of 7.15 days (interquartile range 3.8-10.3 days). Among indications for ECMO cannulation, 12 (25.5%) were cardiac, 23 (48.9%) were respiratory, and 12 (25.5%) were extracorporeal cardiopulmonary resuscitation cannulations. There were 33 (70.2%) veno-arterial cannulations of which 14 (42%) were transthoracic cannulations. There were 13 patients (27.7%) with an overall incidence of stroke: 8 patients had exclusive ischemic strokes, 2 had hemorrhagic strokes, and 3 had mixed types of stroke. The number of strokes in patients on veno-arterial ECMO was significantly decreased in patients undergoing transthoracic cannulation when compared with peripheral cannulation (7 vs. 42%, p = 0.05). Further study will be used to identify risk factors for neurological injury after ECMO and to look for outcome predictors based on neuroradiologic findings.

Introduction: At our institution, the pediatric stroke alert activations started in April 2011 to allow for rapid evaluation and imaging of children presenting within 48 hours with acute stroke symptoms. In a previously published paper, stroke alerts initiated in the pediatric emergency department confirmed strokes in 25% of children. The purpose of this study was to characterize pediatric stroke alerts in hospitalized children. Methods: Demographic and clinical information was obtained from a quality improvement database and medical records for patients (28 days -20 years) at a single institution. Stroke alerts were activated after hospital admission from April 2011 through December 2016. A stroke alert activation means that a neurology resident sees the patient within 15 minutes and MRI is acutely made available. All values were assessed with descriptive statistics. Results: There were 56 in-hospital stroke alerts (mean age 7.5 y, SD 6.1y, 52% male) over 5.75 years. Stroke was the final diagnosis for 25 (45%) children, 72% ischemic, 28% hemorrhage (Figure 1). Other diagnoses included other neurological urgencies including seizure (21%), posterior reversible encephalopathy syndrome (9%), transient ischemic attack (5%) and acute demyelinating encephalomyelitis (4%). Of 25 actual strokes, 68% were stroke alerts initiated by the pediatric ICU or pediatric cardiac ICU. Rapid imaging was completed in 91% of stroke alerts; MRI brain was the 1 st image in 55%. Nine of 25 children with stroke died (36%); 4 secondary to the stroke and the remainder were critically ill prior to stroke diagnosis. Conclusions: Pediatric in-hospital stroke alerts were confirmed stroke in 45% of children, while 38% were other neurological conditions requiring urgent neurologic evaluation. The high frequency of stroke and other serious illnesses in already hospitalized children demonstrates the importance of rapid evaluation via a pediatric stroke alert protocol when stroke is suspected.

OBJECTIVEModern surgical planning and prognostication requires the most accurate outcomes data to practice evidence-based medicine. For clinicians treating children following traumatic brain injury (TBI) these data are severely lacking. The first aim of this study was to assess published CT classification systems in the authors’ pediatric cohort. A pediatric-specific machine-learning algorithm called an artificial neural network (ANN) was then created that robustly outperformed traditional CT classification systems in predicting TBI outcomes in children.METHODSThe clinical records of children under the age of 18 who suffered a TBI and underwent head CT within 24 hours after TBI (n = 565) were retrospectively reviewed.RESULTS“Favorable” outcome (alive with Glasgow Outcome Scale [GOS] score ≥ 4 at 6 months postinjury, n = 533) and “unfavorable” outcome (death at 6 months or GOS score ≤ 3 at 6 months postinjury, n = 32) were used as the primary outcomes. The area under the receiver operating characteristic (ROC) curve (AUC) was used to delineate the strength of each CT grading system in predicting survival (Helsinki, 0.814; Rotterdam, 0.838; and Marshall, 0.781). The AUC for CT score in predicting GOS score ≤ 3, a measure of overall functionality, was similarly predictive (Helsinki, 0.717; Rotterdam, 0.748; and Marshall, 0.663). An ANN was then constructed that was able to predict 6-month outcomes with profound accuracy (AUC = 0.9462 ± 0.0422).CONCLUSIONSThis study showed that machine-learning can be leveraged to more accurately predict TBI outcomes in children.

γ-Glutamylcysteine (γ-GC) is an intermediate molecule of the glutathione (GSH) synthesis pathway. In the present study, we tested the hypothesis that γ-GC pretreatment in cultured astrocytes and neurons protects against hydrogen peroxide (H(2)O(2))-induced oxidative injury. We demonstrate that pretreatment with γ-GC increases the ratio of reduced:oxidized GSH levels in both neurons and astrocytes and increases total GSH levels in neurons. In addition, γ-GC pretreatment decreases isoprostane formation both in neurons and astrocytes, as well as nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation in astrocytes in response to H(2)O(2)-induced oxidative stress. Furthermore, GSH and isoprostane levels significantly correlate with increased neuron and astrocyte viability in cells pretreated with γ-GC. Finally, we demonstrate that administration of a single intravenous injection of γ-GC to mice significantly increases GSH levels in the brain, heart, lungs, liver, and in muscle tissues in vivo. These results support a potential therapeutic role for γ-GC in the reduction of oxidant stress-induced damage in tissues including the brain.

OBJECTThe goal of critical care in treating traumatic brain injury (TBI) is to reduce secondary brain injury by limiting cerebral ischemia and optimizing cerebral blood flow. The authors compared short-term outcomes as defined by discharge disposition and Glasgow Outcome Scale scores in children with TBI before and after the implementation of a protocol that standardized decision-making and interventions among neurosurgeons and pediatric intensivists.METHODSThe authors performed a retrospective pre- and postprotocol study of 128 pediatric patients with severe TBI, as defined by Glasgow Coma Scale (GCS) scores < 8, admitted to a tertiary care center pediatric critical care unit between April 1, 2008, and May 31, 2014. The preprotocol group included 99 patients, and the postprotocol group included 29 patients. The primary outcome of interest was discharge disposition before and after protocol implementation, which took place on April 1, 2013. Ordered logistic regression was used to assess outcomes while accounting for injury severity and clinical parameters. Favorable discharge disposition included discharge home. Unfavorable discharge disposition included discharge to an inpatient facility or death.RESULTSDemographics were similar between the treatment periods, as was injury severity as assessed by GCS score (mean 5.43 preprotocol, mean 5.28 postprotocol; p = 0.67). The ordered logistic regression model demonstrated an odds ratio of 4.0 of increasingly favorable outcome in the postprotocol cohort (p = 0.007). Prior to protocol implementation, 63 patients (64%) had unfavorable discharge disposition and 36 patients (36%) had favorable discharge disposition. After protocol implementation, 9 patients (31%) had unfavorable disposition, while 20 patients (69%) had favorable disposition (p = 0.002). In the preprotocol group, 31 patients (31%) died while 6 patients (21%) died after protocol implementation (p = 0.04).CONCLUSIONSDischarge disposition and mortality rates in pediatric patients with severe TBI improved after implementation of a standardized protocol among caregivers based on best-practice guidelines.

The bidirectional Glenn (BDG) procedure involves the anastomosis of the superior vena cava (SVC) to the pulmonary artery, increasing central venous pressure (CVP). We hypothesize that this increase in CVP triggers an acute neurologic insult, leading to ventriculomegaly. In this retrospective analysis in a tertiary care children’s hospital, we identified 167 patients who underwent the BDG procedure between August 2006 and July 2013. Within this initial cohort, 24 patients had head imaging (CT, MRI, or ultrasound) performed both before and after the BDG. From head imaging available from these 24 patients, we measured the frontal-occipital horn ratio (FOR), a well-validated measure of lateral ventricle size. Using central venous catheter data, we assessed postoperative CVP at 12, 24, and 48 h. Paired t tests and linear regression were used to evaluate our cohort. Median age at surgery was 4.9 months. Paired analysis revealed that median FOR significantly increased between preoperative (median 0.38, IQR 0.37–0.41) and postoperative (median 0.42, IQR 0.40–0.45) head images (p = 0.005). Increasing change in FOR was associated with increased 12-h (R 2 = 0.369, p = 0.003) but not 24- or 48-h postoperative CVP. To our knowledge, our study is the first to demonstrate ventriculomegaly developing after the BDG. Physiologically, increasing CVP after the BDG was associated with greater change in lateral ventricle size. This supports the contention that increasing CVP produced during the BDG may damage the developing brain. This study has informed a prospective evaluation of a link between the BDG procedure and neurologic outcomes.

Using human autoimmune sera as molecular probes, we previously described the association of phosphorylated serine/arginine splicing factors (SR splicing factors) with the U1-small nuclear ribonucleoprotein (U1-snRNP) and U3-small nucleolar RNP (snoRNP) in apoptotic cells. SR proteins are highly conserved autoantigens whose activity is tightly regulated by reversible phosphorylation of serine residues by at least eight different SR protein kinase kinases (SRPKs), including SRPK1, SRPK2, and the scleroderma autoantigen topoisomerase I. In this report, we demonstrate that only one of the known SRPKs, SRPK1, is associated with the U1-snRNP autoantigen complex in healthy and apoptotic cells. SRPK1 is activated early during apoptosis, followed by caspase-mediated proteolytic inactivation at later time points. SRPKs are cleaved in vivo after multiple apoptotic stimuli, and cleavage can be inhibited by overexpression of bcl-2 and bcl-xL, and by exposure to soluble peptide caspase inhibitors. Incubation of recombinant caspases with in vitro–translated SRPKs demonstrates that SRPK1 and SRPK2 are in vitro substrates for caspases-8 and -9, respectively. In contrast, topoisomerase I is cleaved by downstream caspases (-3 and -6). Since each of these SRPKs sits at a distinct checkpoint in the caspase cascade, SRPKs may serve an important role in signaling pathways governing apoptosis, alternative mRNA splicing, SR protein trafficking, RNA stability, and possibly the generation of autoantibodies directed against splicing factors.

Introduction In 2013, our institution established a multidisciplinary pediatric neurovascular conference for coordination of care. Here, we review our initial experience. Methods Clinical and demographic data were obtained from medical records for patients presented to the pediatric neurovascular conference from April 2013 to July 2014. Patient descriptive characteristics were described by mean and standard deviation for continuous measures and by number and percent for categorical measures. Patients were secondarily stratified by lesion/disease type, and descriptive statistics were used to measure demographic and clinical variables. Results The pediatric neurovascular conference met 26 times in the study period. Overall, 75 children were presented to the conference over a 15-month period. The mean age was 9.8 (standard deviation, 6.3) years. There were 42 (56%) male patients. These 75 children were presented a total of 112 times. There were 28 (37%) patients with history of stroke. Complex vascular lesions were the most frequently discussed entity; of 62 children (83%) with a diagnosed vascular lesion, brain arteriovenous malformation (29%), cavernous malformation (15%), and moyamoya (11%) were most common. Most discussions were for review of imaging (35%), treatment plan formulation (27%), the need for additional imaging (25%), or diagnosis (13%). Standardized care protocols for arteriovenous malformation and moyamoya were developed. Conclusion A multidisciplinary conference among a diverse group of providers guides complex care decisions, helps standardize care protocols, promotes provider collaboration, and supports continuity of care in pediatric neurovascular disease.

In this modern society, it is hard to believe that car seats, seat belts, and airbags were once nonexistent. However, other safety initiatives such as motorcycle helmets have still not become law across all states. (Currently in our home state of Tennessee, there is a bill approaching the legislative table that would make them optional.) As with many safety devices and public health initiatives, injuries have led to litigation, which then led to legislation. Not every time, but often enough. Those of us involved in managing child brain and spine injuries have no doubt seen a rise in TV-toppling injuries. It has spurred many of us to wonder if there was some way to effect change, through better base design, material engineering, and/or education. In their accompanying article, Cusimano and Parker are to be commended for bringing these publications together for the common good and using public health methodology to suggest a path forward. The number of TVs in US households is continually increasing, with an estimated 115.6 million TV-containing households, representing 96.7% of all US households. Likewise, the US Consumer Product Safety Commission reports that TV-toppling injuries have been increasing in frequency since 2006. Serious TV-toppling injuries are most commonly seen in preschool-age children, and an estimated 44% of these injuries are related to the head. Given the vulnerability of this population as well as the potential for serious harm, TV-toppling injuries represent a growing public health concern in the area of preventable injuries. In their article on head injuries related to TV sets, Cusimano and Parker report findings from a systematic review of the existing literature on TV-toppling injuries. Their findings demonstrate that injuries related to TVs occur frequently and that toddlers represent the population segment most at risk for serious injury. In addition, they report that the vast majority of these injuries occur during an unwitnessed event within the home and are due to improper placement of the TV, climbing, or collisions with the TV. As part of their report, the authors analyze their findings using Haddon’s Matrix to identify strategies that can modify host and environmental factors to decrease the rate of TV-toppling injuries. Language: en

Proteins cleaved by apoptotic caspases are commonly recognized by autoantibodies found in the serum of patients with rheumatic disease. We report that the 72-kDa signal recognition particle (SRP) protein, a rare target of autoantibodies found in the serum of patients with dermatomyositis and systemic lupus erythematosus, is rapidly cleaved in Jurkat T cells treated with apoptotic (i.e. Fas ligation, treatment with gamma or ultraviolet radiation, or co-culture with anisomycin or staurosporine) but not proliferative (CD3 cross-linking) stimuli. Cleavage of SRP 72 produces a 66-kDa amino-terminal fragment and a 6-kDa carboxyl-terminal fragment that is selectively phosphorylated on serine residues. Cleavage of SRP 72 is prevented by chemical and peptide caspase inhibitors, and by overexpression of bcl-2, an inhibitor of apoptotic cell death. Analysis of the carboxyl terminus of SRP 72 has identified a putative cleavage site (SELD/A) for group III caspases, and carboxyl-terminal serine residues that are highly conserved in phylogeny. Both serine phosphorylation and caspase cleavage of SRP 72 are observed in cells derived from human, dog, rat, and mouse. Canine SRP 72 is cleaved in vitro by recombinant caspase 3 but retains the ability to mediate transport of a signal peptide-containing protein into the endoplasmic reticulum lumen. The 72-kDa component of the SRP joins a growing list of autoantigens that undergo post-translational modifications during programmed cell death.

Glutathione plays a crucial role in free radical scavenging, oxidative injury, and cellular homeostasis. Previously, we identified a non-synonymous polymorphism (P462S) in the gene encoding the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme in glutathione biosynthesis. This polymorphism is present only in individuals of African descent. Presently, we report that this ethnic-specific polymorphism (462S) encodes an enzyme with significantly decreased in vitro activity when expressed by either a bacterial or mammalian cell expression system. In addition, overexpression of the 462P wild-type GCLC enzyme results in higher intracellular glutathione concentrations than overexpression of the 462S isoform. We also demonstrate that apoptotically stimulated mammalian cells overexpressing the 462S enzyme have increased caspase activation and increased DNA laddering compared to cells overexpressing the wild-type 462P enzyme. Finally, we genotyped several African and African-descent populations and demonstrate that the 462S polymorphism is in Hardy-Weinberg disequilibrium, with no individuals homozygous for the 462S polymorphism identified. These findings describe a glutathione production pathway polymorphism present in individuals of African descent with significantly decreased in vitro activity.