Noninvasive Positive Pressure Ventilation Use and In-Hospital Cardiac Arrest in Bronchiolitis.

IMPORTANCE: A recent study showed an association between high hospital-level noninvasive positive pressure ventilation (NIPPV) use and in-hospital cardiac arrest (IHCA) in children with bronchiolitis. OBJECTIVES: We aimed to determine if patient-level exposure to NIPPV in children with bronchiolitis was associated with IHCA. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study at a single-center quaternary PICU in North America including children with International Classification of Diseases primary or secondary diagnoses of bronchiolitis in the Virtual Pediatric Systems database. MAIN OUTCOMES AND MEASURES: The primary exposure was NIPPV and the primary outcome was IHCA. MEASUREMENTS AND MAIN RESULTS: Of 4698 eligible ICU admissions with bronchiolitis diagnoses, IHCA occurred in 1.2% (57/4698). At IHCA onset, invasive mechanical ventilation (IMV) was the most frequent level of respiratory support (65%, 37/57), with 12% (7/57) receiving NIPPV. Patients with IHCA had higher Pediatric Risk of Mortality-III scores (3 [0-8] vs. 0 [0-2]; p < 0.001), more frequently had a complex chronic condition (94.7% vs. 46.2%; p < 0.001), and had higher mortality (21.1% vs. 1.0%; p < 0.001) compared with patients without IHCA. Return of spontaneous circulation (ROSC) was achieved in 93% (53/57) of IHCAs; 79% (45/57) survived to hospital discharge. All seven children without chronic medical conditions and with active bronchiolitis symptoms at the time of IHCA achieved ROSC, and 86% (6/7) survived to discharge. In multivariable analysis restricted to patients receiving NIPPV or IMV, NIPPV exposure was associated with lower odds of IHCA (adjusted odds ratio [aOR], 0.07; 95% CI, 0.03-0.18) compared with IMV. In secondary analysis evaluating categorical respiratory support in all patients, compared with IMV, NIPPV was associated with lower odds of IHCA (aOR, 0.35; 95% CI, 0.14-0.87), whereas no difference was found for minimal respiratory support (none/nasal cannula/humidified high-flow nasal cannula [aOR, 0.56; 95% CI, 0.23-1.36]). CONCLUSIONS AND RELEVANCE: Cardiac arrest in children with bronchiolitis is uncommon, occurring in 1.2% of bronchiolitis ICU admissions. NIPPV use in children with bronchiolitis was associated with lower odds of IHCA.

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.

Pediatric in-hospital cardiac arrest: Respiratory failure characteristics and association with outcomes.

AIMS: To characterize respiratory failure prior to pediatric in-hospital cardiac arrest (IHCA) and to associate pre-arrest respiratory failure characteristics with survival outcomes. METHODS: This is a single-center, retrospective cohort study from a prospectively identified cohort of children <18 years in intensive care units (ICUs) who received cardiopulmonary resuscitation (CPR) for ≥1 minute between January 1, 2017 and June 30, 2021, and were receiving invasive mechanical ventilation (IMV) in the hour prior to IHCA. Patient characteristics, ventilatory support and gas exchange immediately pre-arrest were described and their association with the return of spontaneous circulation (ROSC) was measured. RESULTS: In the 187 events among 154 individual patients, the median age was 0.9 [0.2, 2.4] years, and CPR duration was 7.5 [3, 29] minutes. Respiratory failure was acute prior to 106/187 (56.7%) events, and the primary indication for IMV was respiratory in nature in 107/187 (57.2%) events. Immediately pre-arrest, the median positive end-expiratory pressure was 8 [5, 10] cmH2O; mean airway pressure was 13 [10,18] cmH2O; peak inspiratory pressure was 28 [24, 35] cmH2O; and fraction of inhaled oxygen (FiO2) was 0.40 [0.25, 0.80]. Pre-arrest FiO2 was lower in patients with ROSC vs. without ROSC (0.30 vs. 0.99; p < 0.001). Patients without ROSC had greater severity of pre-arrest oxygenation failure (p < 0.001) as defined by oxygenation index, oxygen saturation index, P/F ratio or S/F ratio. CONCLUSIONS: There was substantial heterogeneity in respiratory failure characteristics and ventilatory requirements pre-arrest. Higher pre-arrest oxygen requirement and greater degree of oxygenation failure were associated with worse survival outcomes.

Clinician-reported physiologic monitoring of cardiopulmonary resuscitation quality during pediatric in-hospital cardiac arrest: A propensity-weighted cohort study.

AIMS: The primary objective was to determine the association between clinician-reported use of end-tidal CO2 (ETCO2) or diastolic blood pressure (DBP) to monitor cardiopulmonary resuscitation (CPR) quality during pediatric in-hospital cardiac arrest (pIHCA) and survival outcomes. DESIGN: A retrospective cohort study was performed in two cohorts: (1) Patients with an invasive airway in place at the time of arrest to evaluate ETCO2 use, and (2) patients with an arterial line in place at the time of arrest to evaluate DBP use. The primary exposure was clinician-reported use of ETCO2 or DBP. The primary outcome was return of spontaneous circulation (ROSC). Propensity-weighted logistic regression evaluated the association between monitoring and outcomes. SETTING: Hospitals reporting to the American Heart Association's Get With The Guidelines®- Resuscitation registry (2007-2021). PATIENTS: Children with index IHCA with an invasive airway or arterial line at the time of arrest. RESULTS: Between January 2007 and May 2021, there were 15,280 pediatric CPR events with an invasive airway or arterial line in place at the time of arrest. Of 7159 events with an invasive airway, 6829 were eligible for analysis. Of 2978 events with an arterial line, 2886 were eligible. Clinicians reported using ETCO2 in 1335/6829 (20%) arrests and DBP in 1041/2886 (36%). Neither exposure was associated with ROSC. ETCO2 monitoring was associated with higher odds of 24-hour survival (aOR 1.17 [1.02, 1.35], p = 0.03). CONCLUSIONS: Neither clinician-reported ETCO2 monitoring nor DBP monitoring during pIHCA were associated with ROSC. Monitoring of ETCO2 was associated with 24-hour survival.

Weight-Based Versus Flat Dosing of Epinephrine During Cardiac Arrest in the PICU: A Multicenter Survey.

OBJECTIVES: Pediatric Advanced Life Support (PALS) guidelines include weight-based epinephrine dosing recommendations of 0.01 mg/kg with a maximum of 1 mg, which corresponds to a weight of 100 kg. Actual practice patterns are unknown. DESIGN: Multicenter cross-sectional survey regarding institutional practices for the transition from weight-based to flat dosing of epinephrine during cardiopulmonary resuscitation in PICUs. Exploratory analyses compared epinephrine dosing practices with several institutional characteristics using Fisher exact test. SETTING: Internet-based survey. SUBJECTS: U.S. PICU representatives (one per institution) involved in resuscitation systems of care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 137 institutions surveyed, 68 (50%) responded. Most responding institutions are freestanding children's hospitals or dedicated children's hospitals within combined adult/pediatric hospitals (67; 99%); 55 (81%) are academic and 41 (60%) have PICU fellowship programs. Among respondents, institutional roles include PICU medical director (13; 19%), resuscitation committee member (23; 34%), and attending physician with interest in resuscitation (21; 31%). When choosing between weight-based and flat dosing, 64 respondents (94%) report using patient weight, 23 (34%) patient age, and five (7%) patient pubertal stage. Among those reporting using weight, 28 (44%) switch at 50 to less than 60 kg, 17 (27%) at 60 to less than 80 kg, five (8%) at 80 to less than 100 kg, and eight (12%) at greater than or equal to 100 kg. Among those reporting using age, four (17%) switch at 14 to less than 16 years, five (22%) at 16 to less than 18, and six (26%) at greater than or equal to 18. Twenty-nine respondents (43%) report using ideal body weight when dosing epinephrine in obese patients. Using patient age in choosing epinephrine dosing is more common in institutions that require Advanced Cardiac Life Support (ACLS) certification for some/all code team responders compared with institutions that do not require ACLS certification (52% vs 22%; p = 0.02). CONCLUSIONS: The majority of PICUs surveyed report epinephrine dosing practices that are inconsistent with PALS guidelines.

The Effect of Epinephrine Dosing Intervals on Outcomes from Pediatric In-Hospital Cardiac Arrest.

Rationale: Animal studies of cardiac arrest suggest that shorter epinephrine dosing intervals than currently recommended (every 3-5 min) may be beneficial in select circumstances. Objectives: To evaluate the association between epinephrine dosing intervals and pediatric cardiac arrest outcomes. Methods: Single-center retrospective cohort study of children (<18 years of age) who received ⩾1 minute of cardiopulmonary resuscitation and ⩾2 doses of epinephrine for an index in-hospital cardiac arrest. Exposure was epinephrine dosing interval ⩽2 minutes (frequent epinephrine) versus >2 minutes. The primary outcome was survival to hospital discharge with a favorable neurobehavioral outcome (Pediatric Cerebral Performance Category score 1-2 or unchanged). Logistic regression evaluated the association between dosing interval and outcomes; additional analyses explored duration of cardiopulmonary resuscitation (CPR) as a mediator. In a subgroup, the effect of dosing interval on diastolic blood pressure was investigated. Measurements and Main Results: Between January 2011 and December 2018, 125 patients met inclusion/exclusion criteria; 33 (26%) received frequent epinephrine. Frequent epinephrine was associated with increased odds of survival with favorable neurobehavioral outcome (adjusted odds ratio, 2.56; 95% confidence interval, 1.07-6.14; P = 0.036), with 66% of the association mediated by CPR duration. Delta diastolic blood pressure was greater after the second dose of epinephrine among patients who received frequent epinephrine (median [interquartile range], 6.3 [4.1 to 16.9] vs. 0.13 [-2.3 to 1.9] mm Hg; P = 0.034). Conclusions: In patients who received at least two doses of epinephrine, dosing intervals ⩽2 minutes were associated with improved neurobehavioral outcomes compared with dosing intervals >2 minutes. Mediation analysis suggests that improved outcomes are largely due to frequent epinephrine shortening duration of CPR.

Pediatric Resuscitation Practices During the Coronavirus Disease 2019 Pandemic.

OBJECTIVES: While most pediatric coronavirus disease 2019 cases are not life threatening, some children have severe disease requiring emergent resuscitative interventions. Resuscitation events present risks to healthcare provider safety and the potential for compromised patient care. Current resuscitation practices and policies for children with suspected/confirmed coronavirus disease 2019 are unknown. DESIGN: Multi-institutional survey regarding inpatient resuscitation practices during the coronavirus disease 2019 pandemic. SETTING: Internet-based survey. SUBJECTS: U.S. PICU representatives (one per institution) involved in resuscitation system planning and oversight. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 130 institutions surveyed, 78 (60%) responded. Forty-eight centers (62%) had admitted coronavirus disease 2019 patients; 26 (33%) reported code team activation for patients with suspected/confirmed coronavirus disease 2019. Sixty-seven respondents (86%) implemented changes to inpatient emergency response systems. The most common changes were as follows: limited number of personnel entering patient rooms (75; 96%), limited resident involvement (71; 91%), and new or refined team roles (74; 95%). New or adapted technology is being used for coronavirus disease 2019 resuscitations in 58 centers (74%). Most institutions (57; 73%) are using enhanced personal protective equipment for all coronavirus disease 2019 resuscitation events; 18 (23%) have personal protective equipment policies dependent on the performance of aerosol generating procedures. Due to coronavirus disease 2019, most respondents are intubating earlier during cardiopulmonary resuscitation (56; 72%), utilizing video laryngoscopy (67; 86%), pausing chest compressions during laryngoscopy (56; 72%), and leaving patients connected to the ventilator during cardiopulmonary resuscitation (56; 72%). Responses were varied regarding airway personnel, prone cardiopulmonary resuscitation, ventilation strategy during cardiopulmonary resuscitation without an airway in place, and extracorporeal cardiopulmonary resuscitation. Most institutions (46; 59%) do not have policies regarding limitations of resuscitation efforts in coronavirus disease 2019 patients. CONCLUSIONS: Most U.S. pediatric institutions rapidly adapted their resuscitation systems and practices in response to the coronavirus disease 2019 pandemic. Changes were commonly related to team members and roles, personal protective equipment, and airway and breathing management, reflecting attempts to balance quality resuscitation with healthcare provider safety.

R5X4 HIV-1 coreceptor use in primary target cells: implications for coreceptor entry blocking strategies.

Entry coreceptor use by HIV-1 plays a pivotal role in viral transmission, pathogenesis and disease progression. In many HIV-1 infected individuals, there is an expansion in coreceptor use from CCR5 to include CXCR4, which is associated with accelerated disease progression. While targeting HIV-1 envelope interactions with coreceptor during viral entry is an appealing approach to combat the virus, the methods of determining coreceptor use and the changes in coreceptor use that can occur during disease progression are important factors that may complicate the use of therapies targeting this stage of HIV-1 replication. Indicator cells are typically used to determine coreceptor use by HIV-1 in vitro, but the coreceptors used on these cells can differ from those used on primary cell targets. V3 based genetic sequence algorithms are another method used to predict coreceptor use by HIV-1 strains. However, these algorithms were developed to predict coreceptor use in cell lines and not primary cells and, furthermore, are not highly accurate for some classes of viruses. This article focuses on R5X4 HIV-1, the earliest CXCR4-using variants, reviewing the pattern of coreceptor use on primary CD4+ lymphocytes and macrophages, the relationship between primary cell coreceptor use and the two principal approaches to coreceptor analysis (genetic prediction and indicator cell phenotyping), and the implications of primary cell coreceptor use by these strains for treatment with a new class of small molecule antagonists that inhibit CCR5-mediated entry. These are important questions to consider given the development of new CCR5 blocking therapies and the prognosis associated with CXCR4 use.

Constrained use of CCR5 on CD4+ lymphocytes by R5X4 HIV-1: efficiency of Env-CCR5 interactions and low CCR5 expression determine a range of restricted CCR5-mediated entry.

R5X4 HIV-1 has impaired utilization of CCR5 on primary CD4+ lymphocytes but the mechanisms responsible are not well defined. Using a panel of diverse R5X4 Envs we identified a spectrum of CCR5 use on CD4+ lymphocytes. Greater lymphocyte CCR5 use correlated with relative resistance to CCR5 mAbs and small molecule antagonists. Increasing CCR5 expression on lymphocytes increased the proportion of entry mediated by CCR5 for all R5X4 isolates except 89.6. In cell lines with regulated CCR5 expression, strains with greater lymphocyte CCR5 use better exploited limiting levels of CCR5. Introduction of an R306S mutation in the 89.6 V3 domain enhanced its utilization of CCR5 at low levels and switched its preference to CCR5 for lymphocyte entry. Thus, the degree to which R5X4 HIV-1 use primary lymphocyte CCR5 is determined by low CCR5 expression coupled with variations in the efficiency of Env-CCR5 interactions, which is in part governed by V3 sequences.

Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1 alpha through Lyn kinase.

Infiltration of activated monocytes into the brain is a prerequisite for the development of various neurological disorders such as HIV-associated dementia, multiple sclerosis, and other inflammatory processes. In these pathologies, the chemokine SDF-1alpha (CXCL12) is over-expressed and might attract monocytes into the CNS. We demonstrate here that SDF-1alpha stimulates migration of monocytes through its receptor, CXCR4, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta(2) integrins. SDF-1alpha also decreases monocyte adherence to brain microvascular endothelial cells (BMVEC) that are activated with TNF-alpha, IL-1beta, or recombinant envelope glycoprotein from HIV-1, which increase BMVEC expression of ICAM-1. The decreased adherence is linked to down-regulation on monocytes of the activation-dependent epitope of the beta(2) integrin LFA-1 by SDF-1alpha. Knockdown of Lyn in monocytes using small interfering RNA decreases SDF-1alpha-mediated migration and prevents the inhibition of monocyte attachment to ICAM-1 and activated BMVEC. Thus, in SDF-1alpha-stimulated monocytes, Lyn acts as a positive regulator of migration and a negative regulator of adhesion to BMVEC through the LFA-1 integrin. These results provide a novel Lyn-mediated signaling mechanism for the regulation of monocyte movement at the blood-brain barrier.

Chronic tempol prevents hypertension, proteinuria, and poor feto-placental outcomes in BPH/5 mouse model of preeclampsia.

Recently we described a mouse model, BPH/5, that spontaneously develops the hallmark clinical features of preeclampsia. BPH/5 exhibit impaired placentation before the onset of hypertension and proteinuria, supporting a causal role for the placenta in the pathogenesis of preeclampsia. Here we tested the hypothesis that an increase in reactive oxygen species (ROS) early in pregnancy results in placental abnormalities leading to the maternal symptoms of preeclampsia. We further hypothesized that chronic antioxidant therapy would ameliorate both feto-placental abnormalities and maternal symptoms. ROS levels measured by dihydroethidium revealed significant increases in oxidative stress in BPH/5 placentas at midgestation compared with C57 controls. This increase in ROS was correlated with reduced expression and activity of cytoplasmic superoxide dismutase in early and midgestation BPH/5 placentas. These abnormalities in placental oxidant factors occurred before the onset of maternal symptoms, suggesting a possible causal link between increased ROS and maternal and feto-placental pathology in this model. In support of this, chronic treatment of BPH/5 with the superoxide dismutase-mimetic Tempol throughout gestation significantly improved fetal growth and survival. Furthermore, Tempol ameliorated pregnancy-induced increases in blood pressure and proteinuria in BPH/5 mothers. We confirmed that Tempol radical was present in plasma, and it normalized ROS levels in all placental zones in BPH/5. These data for the first time demonstrate an important causative role for increased ROS in the placenta in the pathogenesis of preeclampsia in a model that spontaneously develops the disease. The results also strongly suggest the potential utility of antioxidant therapy in treating preeclampsia.

Severe feto-placental abnormalities precede the onset of hypertension and proteinuria in a mouse model of preeclampsia.

Preeclampsia is a prevalent and potentially devastating disorder of pregnancy. Characterized by a sudden spike in blood pressure and urinary protein levels, it is associated with significant obstetric complications. BPH/5 is an inbred mouse model of preeclampsia with borderline hypertension before pregnancy. BPH/5 mice develop hypertension, proteinuria, and endothelial dysfunction during late gestation (after E14.5). We hypothesized that BPH/5 mice might exhibit early feto-placental abnormalities before the onset of maternal disease. All placental cell lineages were present in BPH/5 mice. However, the fetal and placental weights were reduced, with abnormalities in all the placental zones observed starting early in gestation (E9.5-E12.5). The fractional area occupied by the junctional zone was significantly reduced at all gestational timepoints. Markedly fewer CDKN1C-stained trophoblasts were seen invading the proximal decidual zone, and this was accompanied by reductions in Cdkn1c gene expression. Trophoblast giant cell morphology and cytokeratin staining were not altered, although the mRNA levels of several giant cell-specific markers were significantly downregulated. The labyrinth layer displayed decreased branching morphogenesis of endothelial cells, with electron microscopy evidence of attenuated trophoblast layers. The maternal decidual arteries showed increased wall-to-lumen ratios with persistence of actin-positive smooth muscle cells. These changes translated into dramatically increased vascular resistance in the uterine arteries, as measured by pulse-wave Doppler. Collectively, these results support the hypothesis that defects at the maternal-fetal interface are primary causal events in preeclampsia, and further suggest the BPH/5 model is important for investigations of the underlying pathogenic mechanisms in preeclampsia.