Therapeutic Plasma Exchange in Children With Thrombocytopenia-Associated Multiple Organ Failure: The Thrombocytopenia-Associated Multiple Organ Failure Network Prospective Experience.

OBJECTIVE: The objective was to compare the resolution of organ dysfunction, 28-day mortality, and biochemical markers in children with thrombocytopenia-associated multiple organ failure who received therapeutic plasma exchange versus no therapeutic plasma exchange. DESIGN: Observational longitudinal cohort study. SETTING: Nine U.S. PICUs. PATIENTS: Eighty-one children with sepsis-induced thrombocytopenia-associated multiple organ failure. INTERVENTIONS: Therapeutic plasma exchange. MEASUREMENTS AND MAIN RESULTS: Adjusted relative risk for 28-day mortality was modeled using standard multivariate regression with propensity score weighting to reduce covariate confounding. Change from baseline Pediatric Logistic Organ Dysfunction scores between therapeutic plasma exchange and no therapeutic plasma exchange differed in temporal pattern during the first week (p = 0.009). By day 4, mean Pediatric Logistic Organ Dysfunction score declined by 7.9 points (95% CI, -10.8 to -5.1) in the therapeutic plasma exchange-treated group compared with no change with no therapeutic plasma exchange. Use of therapeutic plasma exchange was associated with reduced 28-day mortality by multivariate analysis (adjusted relative risk, 0.45; 95% CI, 0.23-0.90; p = 0.02) and by propensity score weighting (adjusted relative risk, 0.46; 95% CI, 0.22-0.97; p = 0.04). CONCLUSIONS: Therapeutic plasma exchange use in thrombocytopenia-associated multiple organ failure was associated with a decrease in organ dysfunction. After accounting for several risk factors, 28-day all-cause mortality was lower in children treated with therapeutic plasma exchange compared with those receiving no therapeutic plasma exchange. A multicenter randomized clinical trial is necessary to determine a causal relationship.

Cerebrovascular Physiology During Pediatric Extracorporeal Membrane Oxygenation: A Multicenter Study Using Transcranial Doppler Ultrasonography.

OBJECTIVES: To explore changes to expected, age-related transcranial Doppler ultrasound variables during pediatric extracorporeal membrane oxygenation. DESIGN: Prospective, observational, multicenter study. SETTING: Tertiary care PICUs. PATIENTS: Children 1 day to 18 years old requiring veno arterial extracorporeal membrane oxygenation. METHODS: Participants underwent daily transcranial Doppler ultrasound measurement of bilateral middle cerebral artery flow velocities. Acute neurologic injury was diagnosed if seizures, cerebral hemorrhage, or diffuse cerebral ischemia was detected. MEASUREMENTS AND MAIN RESULTS: Fifty-two children were enrolled and analyzed. In the 44 children without acute neurologic injury, there was a significant reduction in systolic flow velocity and mean flow velocity compared with predicted values over time (F [8, 434] = 60.44; p ≤ 0.0001, and F [8, 434] = 17.61; p ≤ 0.0001). Middle cerebral artery systolic flow velocity was lower than predicted on extracorporeal membrane oxygenation days 1-5, and mean flow velocity was lower than predicted on extracorporeal membrane oxygenation days 1-3. In the six infants less than 90 days old suffering diffuse cerebral ischemia, middle cerebral artery systolic flow velocity, mean flow velocity, and diastolic flow velocity from extracorporeal membrane oxygenation days 1-9 were not significantly different when compared with children of similar age in the cohort that did not suffer acute neurologic injury (systolic flow velocity F [8, 52] = 0.6659; p = 0.07 and diastolic flow velocity F [8, 52] = 1.4; p = 0.21 and mean flow velocity F [8, 52] = 1.93; p = 0.07). Pulsatility index was higher in these infants over time than children of similar age in the cohort on extracorporeal membrane oxygenation that did not suffer acute neurologic injury (F [8, 52] = 3.1; p = 0.006). No patient in the study experienced cerebral hemorrhage. CONCLUSIONS: Flow velocities in the middle cerebral arteries of children requiring extracorporeal membrane oxygenation are significantly lower than published normative values for critically ill, mechanically ventilated, sedated children. Significant differences in measured systolic flow velocity, diastolic flow velocity, and mean flow velocity were not identified in children suffering ischemic injury compared with those who did not. However, increased pulsatility index may be a marker for ischemic injury in young infants on extracorporeal membrane oxygenation.

Initiating Nutritional Support Before 72 Hours Is Associated With Favorable Outcome After Severe Traumatic Brain Injury in Children: A Secondary Analysis of a Randomized, Controlled Trial of Therapeutic Hypothermia.

OBJECTIVES: To understand the relationship between the timing of initiation of nutritional support in children with severe traumatic brain injury and outcomes. DESIGN: Secondary analysis of a randomized, controlled trial of therapeutic hypothermia (Pediatric Traumatic Brain Injury Consortium: Hypothermia, also known as "the Cool Kids Trial" (NCT 00222742). SETTINGS: Fifteen clinical sites in the United States, Australia, and New Zealand. SUBJECTS: Inclusion criteria included 1) age less than 18 years, 2) postresuscitation Glasgow Coma Scale less than or equal to 8, 3) Glasgow Coma Scale motor score less than 6, and 4) available to be randomized within 6 hours after injury. Exclusion criteria included normal head CT, Glasgow Coma Scale equals to 3, hypotension for greater than 10 minutes (< fifth percentile for age), uncorrectable coagulopathy, hypoxia (arterial oxygen saturation < 90% for > 30 min), pregnancy, penetrating injury, and unavailability of a parent or guardian to consent at centers without emergency waiver of consent. INTERVENTIONS: Therapeutic hypothermia (32-33°C for 48 hr) followed by slow rewarming for the primary study. For this analysis, the only intervention was the extraction of data regarding nutritional support from the existing database. MEASUREMENTS AND MAIN RESULTS: Timing of initiation of nutritional support was determined and patients stratified into four groups (group 1-no nutritional support over first 7 d; group 2-nutritional support initiated < 48 hr after injury; group 3-nutritional support initiated 48 to < 72 hr after injury; group 4-nutritional support initiated 72-168 hr after injury). Outcomes were also stratified (mortality and Glasgow Outcomes Scale-Extended for Pediatrics; 1-4, 5-7, 8) at 6 and 12 months. Mixed-effects models were performed to define the relationship between nutrition and outcome. Children (n = 90, 77 randomized, 13 run-in) were enrolled (mean Glasgow Coma Scale = 5.8); the mortality rate was 13.3%. 57.8% of subjects received hypothermia Initiation of nutrition before 72 hours was associated with survival (p = 0.01), favorable 6 months Glasgow Outcomes Scale-Extended for Pediatrics (p = 0.03), and favorable 12 months Glasgow Outcomes Scale-Extended for Pediatrics (p = 0.04). Specifically, groups 2 and 3 had favorable outcomes versus group 1. CONCLUSIONS: Initiation of nutritional support before 72 hours after traumatic brain injury was associated with decreased mortality and favorable outcome in this secondary analysis. Although this provides a rationale to initiate nutritional support early after traumatic brain injury, definitive studies that control for important covariates (severity of injury, clinical site, calories delivered, parenteral/enteral routes, and other factors) are needed to provide definitive evidence on the optimization of the timing of nutritional support after severe traumatic brain injury in children.

Age and Mortality in Pediatric Severe Traumatic Brain Injury: Results from an International Study.

BACKGROUND: Although small series have suggested that younger age is associated with less favorable outcome after severe traumatic brain injury (TBI), confounders and biases have limited our understanding of this relationship. We hypothesized that there would be an association between age and mortality in children within an ongoing observational, cohort study. METHODS: The first 200 subjects from the Approaches and Decisions for Acute Pediatric TBI trial were eligible for this analysis (inclusion criteria: severe TBI (Glasgow Coma Scale [GCS] score ≤ 8], age 18 years, and intracranial pressure (ICP) monitor placed; exclusion: pregnancy). Children with suspected abusive head trauma (AHT) were excluded to avoid bias related to the association between AHT and mortality. Demographics, and prehospital and resuscitation events were collected/analyzed, and children were stratified based on age at time of injury (< 5, 5-< 11, 11-18 years) and presented as mean ± standard error of the mean (SEM). Analyses of variance were used to test the equality of the means across the group for continuous variable, and Chi-square tests were used to compare percentages for discrete variables (post hoc comparisons were made using t test and Bonferroni corrections, as needed). Kaplan-Meier curves were generated for each age subgroup describing the time of death, and log-rank was used to compare the curves. Cox proportional hazards regression models were used to assess the effect of age on time to death while controlling for covariates. RESULTS: In the final cohort (n = 155, 45 excluded for AHT), overall age was 9.2 years ± 0.4 and GCS was 5.3 ± 0.1. Mortality was similar between strata (14.0, 20.0, 20.9%, respectively, p = 0.58). Motor vehicle accidents were the most common mechanism across all strata, while falls tended to be more common in the youngest stratum (p = 0.08). The youngest stratum demonstrated increased incidence of spontaneous hypothermia at presentation and decreased hemoglobin concentrations and coagulopathies, while the oldest demonstrated lower platelet counts. CONCLUSIONS: In contrast to previous reports, we failed to detect mortality differences across age strata in children with severe TBI. We have discerned novel associations between age and various markers of injury-unrelated to AHT-that may lead to testable hypotheses in the future.

Delirium in Critically Ill Children: An International Point Prevalence Study.

OBJECTIVES: To determine prevalence of delirium in critically ill children and explore associated risk factors. DESIGN: Multi-institutional point prevalence study. SETTING: Twenty-five pediatric critical care units in the United States, the Netherlands, New Zealand, Australia, and Saudi Arabia. PATIENTS: All children admitted to the pediatric critical care units on designated study days (n = 994). INTERVENTION: Children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the bedside nurse. Demographic and treatment-related variables were collected. MEASUREMENTS AND MAIN RESULTS: Primary study outcome measure was prevalence of delirium. In 159 children, a final determination of mental status could not be ascertained. Of the 835 remaining subjects, 25% screened positive for delirium, 13% were classified as comatose, and 62% were delirium-free and coma-free. Delirium prevalence rates varied significantly with reason for ICU admission, with highest delirium rates found in children admitted with an infectious or inflammatory disorder. For children who were in the PICU for 6 or more days, delirium prevalence rate was 38%. In a multivariate model, risk factors independently associated with development of delirium included age less than 2 years, mechanical ventilation, benzodiazepines, narcotics, use of physical restraints, and exposure to vasopressors and antiepileptics. CONCLUSIONS: Delirium is a prevalent complication of critical illness in children, with identifiable risk factors. Further multi-institutional, longitudinal studies are required to investigate effect of delirium on long-term outcomes and possible preventive and treatment measures. Universal delirium screening is practical and can be implemented in pediatric critical care units.

Hypothermia for pediatric refractory status epilepticus.

PURPOSE: Refractory status epilepticus (RSE) is a life-threatening emergency, demonstrating, by definition, significant pharmacoresistance. We describe five cases of pediatric RSE treated with mild hypothermia. METHODS: Retrospective chart review was performed of records of children who received hypothermia for RSE at two tertiary-care pediatric hospitals between 2009 and 2012. KEY FINDINGS: Five children with RSE received mild hypothermia (32-35°C). Hypothermia reduced seizure burden during and after treatment in all cases. Prior to initiation of hypothermia, four children (80%) received pentobarbital infusions to treat RSE, but relapsed after pentobarbital discontinuation. No child relapsed after treatment with hypothermia. One child died after redirection of care. Remaining four children were discharged. SIGNIFICANCE: This is the largest pediatric case series reporting treatment of RSE with mild hypothermia. Hypothermia decreased seizure burden during and after pediatric RSE and may prevent RSE relapse.

Comparative Effectiveness of Diversion of Cerebrospinal Fluid for Children With Severe Traumatic Brain Injury.

Importance: 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. Objective: 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. Design, Setting, and Participants: 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. Exposures: 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). Main Outcomes and Measures: 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. Results: 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). Conclusions and Relevance: 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.

Multiplex assessment of cytokine and chemokine levels in cerebrospinal fluid following severe pediatric traumatic brain injury: effects of moderate hypothermia.

This study performed a comprehensive analysis of cerebrospinal fluid (CSF) cytokine levels after severe traumatic brain injury (TBI) in children using a multiplex bead array assay and to evaluate the effects of moderate hypothermia on cytokine levels. To this end, samples were collected during two prospective randomized controlled trials of therapeutic moderate hypothermia in pediatric TBI. Thirty-six children with severe TBI (Glasgow Coma Scale [GCS] score of

Feasibility Study Evaluating Therapeutic Hypothermia for Refractory Status Epilepticus in Children.

Pediatric refractory status epilepticus (RSE) is a neurological emergency with significant morbidity and mortality, which lacks consensus regarding diagnosis and treatment(s). Therapeutic hypothermia (TH) is an effective treatment for RSE in preclinical models and small series. In addition, TH is a standard care for adults after cardiac arrest and neonates with hypoxic-ischemic encephalopathy. The purpose of this study was to identify the feasibility of a study of pediatric RSE within a research group (Pediatric Neurocritical Care Research Group [PNCRG]). Pediatric intensive care unit (PICU) admissions at seven centers were prospectively screened from October 2012 to July 2013 for RSE. Experts within the PNCRG estimated that clinicians would be unwilling to enroll a child, unless the child required at least two different antiepileptic medications and a continuous infusion of another antiepileptic medication with ongoing electrographic seizure activity for ≥2 hours after continuous infusion initiation. Data for children meeting the above inclusion criteria were collected, including the etiology of RSE, history of epilepsy, and maximum dose of continuous antiepileptic infusions. There were 8113 PICU admissions over a cumulative 52 months (October 2012-July 2013) at seven centers. Of these, 69 (0.85%) children met inclusion criteria. Twenty children were excluded due to acute diagnoses affected by TH, contraindications to TH, or lack of commitment to aggressive therapies. Sixteen patients had seizure cessation within 2 hours, resulting in 33 patients who had inadequate seizure control after 2 hours and a continuous antiepileptic infusion. Midazolam (21/33, 64%) and pentobarbital (5/33, 15%) were the most common infusions with a wide maximum dose range. More than one infusion was required for seizure control in four patients. There are substantial numbers of subjects at clinical sites within the PNCRG with RSE that would meet the proposed inclusion criteria for a study of TH. The true feasibility of such a study depends on the sample size necessary to achieve therapeutic effects on justifiable clinical outcomes.

Computed tomography vs magnetic resonance imaging for identifying acute lesions in pediatric traumatic brain injury.

BACKGROUND AND OBJECTIVE: Pediatric traumatic brain injury (TBI) is a leading cause of morbidity and mortality in children. Computed tomography (CT) is the modality of choice to screen for brain injuries. MRI may provide more clinically relevant information. The purpose of this study was to compare lesion detection between CT and MRI after TBI. METHODS: Retrospective cohort of children (0-21 years) with TBI between 2008 and 2010 at a Level 1 pediatric trauma center with a head CT scan on day of injury and a brain MRI scan within 2 weeks of injury. Agreement between CT and MRI was determined by κ statistic and stratified by injury mechanism. RESULTS: One hundred five children were studied. Of these, 78% had mild TBI. The MRI scan was obtained a median of 1 day (interquartile range, 1-2) after CT. Overall, CT and MRI demonstrated poor agreement (κ=-0.083; P=.18). MRI detected a greater number of intraparenchymal lesions (n=36; 34%) compared with CT (n=16; 15%) (P<.001). Among patients with abusive head trauma, MRI detected intraparenchymal lesions in 16 (43%), compared with only 4 (11%) lesions with CT (P=.03). Of 8 subjects with a normal CT scan, 6 out of 8 had abnormal lesions on MRI. CONCLUSIONS: Compared with CT, MRI identified significantly more intraparenchymal lesions in pediatric TBI, particularly in children with abusive head trauma. The prognostic value of identification of intraparenchymal lesions by MRI is unknown but warrants additional inquiry. Risks and benefits from early MRI (including sedation, time, and lack of radiation exposure) compared with CT should be weighed by clinicians.