Ventilator Weaning and Terminal Extubation: Withdrawal of Life-Sustaining Therapy in Children. Secondary Analysis of the Death One Hour After Terminal Extubation Study.

OBJECTIVE: Terminal extubation (TE) and terminal weaning (TW) during withdrawal of life-sustaining therapies (WLSTs) have been described and defined in adults. The recent Death One Hour After Terminal Extubation study aimed to validate a model developed to predict whether a child would die within 1 hour after discontinuation of mechanical ventilation for WLST. Although TW has not been described in children, pre-extubation weaning has been known to occur before WLST, though to what extent is unknown. In this preplanned secondary analysis, we aim to describe/define TE and pre-extubation weaning (PW) in children and compare characteristics of patients who had ventilatory support decreased before WLST with those who did not. DESIGN: Secondary analysis of multicenter retrospective cohort study. SETTING: Ten PICUs in the United States between 2009 and 2021. PATIENTS: Nine hundred thirteen patients 0-21 years old who died after WLST. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: 71.4% ( n = 652) had TE without decrease in ventilatory support in the 6 hours prior. TE without decrease in ventilatory support in the 6 hours prior = 71.4% ( n = 652) of our sample. Clinically relevant decrease in ventilatory support before WLST = 11% ( n = 100), and 17.6% ( n = 161) had likely incidental decrease in ventilatory support before WLST. Relevant ventilator parameters decreased were F io2 and/or ventilator set rates. There were no significant differences in any of the other evaluated patient characteristics between groups (weight, body mass index, unit type, primary diagnostic category, presence of coma, time to death after WLST, analgosedative requirements, postextubation respiratory support modality). CONCLUSIONS: Decreasing ventilatory support before WLST with extubation in children does occur. This practice was not associated with significant differences in palliative analgosedation doses or time to death after extubation.

Invasive Multimodality Neuromonitoring to Manage Cerebral Edema in Pediatric Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory disorder of the CNS with a variety of clinical manifestations, including cerebral edema. Case Summary: A 7-year-old boy presented with headaches, nausea, and somnolence. He was found to have cerebral edema that progressed to brainstem herniation. Invasive multimodality neuromonitoring was initiated to guide management of intracranial hypertension and cerebral hypoxia while he received empiric therapies for neuroinflammation. Workup revealed serum myelin oligodendrocyte glycoprotein antibodies. He survived with a favorable neurologic outcome. Conclusion: We describe a child who presented with cerebral edema and was ultimately diagnosed with MOGAD. Much of his management was guided using data from invasive multimodality neuromonitoring. Invasive multimodality neuromonitoring may have utility in managing life-threatening cerebral edema due to neuroinflammation.

Dramatic Response to Anti-IL-6 Receptor Therapy in Children With Life-Threatening Myelin Oligodendrocyte Glycoprotein-Associated Disease.

OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an immune-mediated neuroinflammatory disorder leading to demyelination of the CNS. Interleukin (IL)-6 receptor blockade is under study in relapsing MOGAD as a preventative strategy, but little is known about the role of such treatment for acute MOGAD attacks. METHODS: We discuss the cases of a 7-year-old boy and a 15-year-old adolescent boy with severe acute CNS demyelination and malignant cerebral edema with early brain herniation associated with clearly positive serum titers of MOG-IgG, whose symptoms were incompletely responsive to standard acute therapies (high-dose steroids, IV immunoglobulins (IVIGs), and therapeutic plasma exchange). RESULTS: Both boys improved quickly with IL-6 receptor inhibition, administered as tocilizumab. Both patients have experienced remarkable neurologic recovery. DISCUSSION: We propose that IL-6 receptor therapies might also be considered in acute severe life-threatening presentations of MOGAD.

Organ Donation From Patients on Extracorporeal Membrane Oxygenation at the Time of Death.

To describe the clinical characteristics and organ donation rate of patients supported by extracorporeal membrane oxygenation (ECMO) at the time of death. DESIGN: Retrospective observational study. Pearson chi-square and Fisher exact tests were used in statistical analyses. SETTING: One hundred twenty-seven acute care hospitals in New Jersey, Pennsylvania, and Delaware. PATIENTS: Adult and pediatric patients who were on ECMO at the time of referral to a large organ procurement organization (OPO) between 2016 and 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nineteen thousand nine hundred thirty patients were referred to the OPO between November 2016 and September 2020, of which 5,034 were medically suitable potential donors. Of this cohort, 143 patients were supported on ECMO at the time of OPO referral and 141 were included in analyses (median age 47 yr, 60% male). Thirty-three percent (46/141, median age 48 yr, 52% male) donated organs, compared with 50% of non-ECMO patients (p ≤ 0.0005). ECMO and non-ECMO patients had organs recovered but not transplanted at similar rates (11% vs 10%, p = 0.8). There were no significant differences in sex (p = 0.16) or ethnicity (p = 0.50) between organ donor and nondonor groups. Fifty-one percent (21/41) of organ donors donated after circulatory death and 49% (20/41) after brain death. Patients declared dead by neurologic criteria were more likely to donate (51%) than those declared dead by circulatory criteria (21%, p < 0.001). Frequency of cardiac arrest prior to ECMO was similar between donors and nondonors (p = 0.68). Thirty-nine percent (16/41) of donors had an out-of-hospital cardiac arrest (OHCA) and 51% (21/41) were cannulated via extracorporeal cardiopulmonary resuscitation (ECPR). The most common reason patients were not donors was that family declined (57%). CONCLUSIONS: One-third of patients referred to the OPO on ECMO at the time of death donated organs. While donation occurred less frequently after ECMO, ECMO and non-ECMO patients had organs used rather than discarded at a similar rate. Patients successfully donated following OHCA and/or ECPR. Clinicians should not consider ECMO a barrier to organ donation.

Association of Diagnostic Stewardship for Blood Cultures in Critically Ill Children With Culture Rates, Antibiotic Use, and Patient Outcomes: Results of the Bright STAR Collaborative.

Importance: Blood culture overuse in the pediatric intensive care unit (PICU) can lead to unnecessary antibiotic use and contribute to antibiotic resistance. Optimizing blood culture practices through diagnostic stewardship may reduce unnecessary blood cultures and antibiotics. Objective: To evaluate the association of a 14-site multidisciplinary PICU blood culture collaborative with culture rates, antibiotic use, and patient outcomes. Design, Setting, and Participants: This prospective quality improvement (QI) collaborative involved 14 PICUs across the United States from 2017 to 2020 for the Bright STAR (Testing Stewardship for Antibiotic Reduction) collaborative. Data were collected from each participating PICU and from the Children's Hospital Association Pediatric Health Information System for prespecified primary and secondary outcomes. Exposures: A local QI program focusing on blood culture practices in the PICU (facilitated by a larger QI collaborative). Main Outcomes and Measures: The primary outcome was blood culture rates (per 1000 patient-days/mo). Secondary outcomes included broad-spectrum antibiotic use (total days of therapy and new initiations of broad-spectrum antibiotics ≥3 days after PICU admission) and PICU rates of central line-associated bloodstream infection (CLABSI), Clostridioides difficile infection, mortality, readmission, length of stay, sepsis, and severe sepsis/septic shock. Results: Across the 14 PICUs, the blood culture rate was 149.4 per 1000 patient-days/mo preimplementation and 100.5 per 1000 patient-days/mo postimplementation, for a 33% relative reduction (95% CI, 26%-39%). Comparing the periods before and after implementation, the rate of broad-spectrum antibiotic use decreased from 506 days to 440 days per 1000 patient-days/mo, respectively, a 13% relative reduction (95% CI, 7%-19%). The broad-spectrum antibiotic initiation rate decreased from 58.1 to 53.6 initiations/1000 patient-days/mo, an 8% relative reduction (95% CI, 4%-11%). Rates of CLABSI decreased from 1.8 to 1.1 per 1000 central venous line days/mo, a 36% relative reduction (95% CI, 20%-49%). Mortality, length of stay, readmission, sepsis, and severe sepsis/septic shock were similar before and after implementation. Conclusions and Relevance: Multidisciplinary diagnostic stewardship interventions can reduce blood culture and antibiotic use in the PICU. Future work will determine optimal strategies for wider-scale dissemination of diagnostic stewardship in this setting while monitoring patient safety and balancing measures.

Pediatric Sudden Unexpected Death in Epilepsy: What Have we Learned from Animal and Human Studies, and Can we Prevent it?

Several factors, such as epilepsy syndrome, poor compliance, and increased seizure frequency increase the risks of sudden unexpected death in epilepsy (SUDEP). Animal models have revealed that the mechanisms of SUDEP involve initially a primary event, often a seizure of sufficient type and severity, that occurs in a brain, which is vulnerable to SUDEP due to either genetic or antecedent factors. This primary event initiates a cascade of secondary events starting, as some models indicate, with cortical spreading depolarization that propagates to the brainstem where it results in autonomic dysfunction. Intrinsic abnormalities in brainstem serotonin, adenosine, sodium-postassium ATPase, and respiratory-control systems are also important. The tertiary event, which results from the above dysfunction, consists of either lethal central apnea, pulmonary edema, or arrhythmia. Currently, it is necessary to (1) continue researching SUDEP mechanisms, (2) work on reducing SUDEP risk factors, and (3) address the major need to counsel families about SUDEP.

Knock-in mouse model of alternating hemiplegia of childhood: behavioral and electrophysiologic characterization.

OBJECTIVES: Mutations in the ATP1α3 subunit of the neuronal Na+/K+-ATPase are thought to be responsible for seizures, hemiplegias, and other symptoms of alternating hemiplegia of childhood (AHC). However, the mechanisms through which ATP1A3 mutations mediate their pathophysiologic consequences are not yet understood. The following hypotheses were investigated: (1) Our novel knock-in mouse carrying the most common heterozygous mutation causing AHC (D801N) will exhibit the manifestations of the human condition and display predisposition to seizures; and (2) the underlying pathophysiology in this mouse model involves increased excitability in response to electrical stimulation of Schaffer collaterals and abnormal predisposition to spreading depression (SD). METHODS: We generated the D801N mutant mouse (Mashlool, Mashl+/-) and compared mutant and wild-type (WT) littermates. Behavioral tests, amygdala kindling, flurothyl-induced seizure threshold, spontaneous recurrent seizures (SRS), and other paroxysmal activities were compared between groups. In vitro electrophysiologic slice experiments on hippocampus were performed to assess predisposition to hyperexcitability and SD. RESULTS: Mutant mice manifested a distinctive phenotype similar to that of humans with AHC. They had abnormal impulsivity, memory, gait, motor coordination, tremor, motor control, endogenous nociceptive response, paroxysmal hemiplegias, diplegias, dystonias, and SRS, as well as predisposition to kindling, to flurothyl-induced seizures, and to sudden unexpected death. Hippocampal slices of mutants, in contrast to WT animals, showed hyperexcitable responses to 1 Hz pulse-trains of electrical stimuli delivered to the Schaffer collaterals and had significantly longer duration of K+-induced SD responses. SIGNIFICANCE: Our model reproduces the major characteristics of human AHC, and indicates that ATP1α3 dysfunction results in abnormal short-term plasticity with increased excitability (potential mechanism for seizures) and a predisposition to more severe SD responses (potential mechanism for hemiplegias). This model of the human condition should help in understanding the molecular pathways underlying these phenotypes and may lead to identification of novel therapeutic strategies of ATP1α3 related disorders and seizures.