Impact of ABCC8 and TRPM4 genetic variation in central nervous system dysfunction associated with pediatric sepsis.

BACKGROUND: Sepsis-associated brain injury is associated with deterioration of mental status, persistent cognitive impairment, and morbidity. The SUR1/TRPM4 channel is a non-selective cation channel that is transcriptionally upregulated in the central nervous system with injury, allowing sodium influx, depolarization, cellular swelling, and secondary injury. We hypothesized that genetic variation in ABCC8 (SUR1 gene) and TRPM4 would associate with central nervous system dysfunction in severe pediatric sepsis. METHODS: 326 children with severe sepsis underwent whole exome sequencing in an observational cohort. We compared children with and without central nervous system dysfunction (Glasgow Coma Scale <12) to assess for associations with clinical characteristics and pooled rare variants in ABCC8 and TRPM4. Sites of variation were mapped onto protein structure and assessed for phenotypic impact. RESULTS: Pooled rare variants in either ABCC8 or TRPM4 associated with decreased odds of central nervous system dysfunction in severe pediatric sepsis (OR 0.14, 95% CI 0.003-0.87), p-value = 0.025). This association persisted following adjustment for race, organ failure, viral infection, and continuous renal replacement therapy (aOR 0.11, 95% CI 0.01-0.59, p-value = 0.038). Structural mapping showed that rare variants concentrated in the nucleotide-binding domains of ABCC8 and N-terminal melastatin homology region of TRPM4. CONCLUSION: This study suggests a role for the ABCC8/TRPM4 channel in central nervous system dysfunction in severe pediatric sepsis. While exploratory, the lack of therapies to prevent or mitigate central nervous system dysfunction in pediatric sepsis warrants further studies to clarify the mechanism and confirm the potential protective effect of these rare ABCC8/TRPM4 variants.

Resuscitation arterial waveform quantification and outcomes in pediatric bidirectional Glenn and Fontan patients.

BACKGROUND: Resuscitation with chest compressions and positive pressure ventilation in Bidirectional Glenn (BDG) or Fontan physiology may compromise passive venous return and accentuate neurologic injury. We hypothesized that arterial pressure and survival would be better in BDG than Fontan patients. METHODS: Secondary analyses of the Pediatric Intensive Care Quality of CPR and Improving Outcomes from Pediatric Cardiac Arrest databases. P-values were considered significant if < 0.05. RESULTS: In total, 64 patients had either BDG (42/64, 66%) or Fontan (22/64, 34%) anatomy. Return of spontaneous circulation was achieved in 76% of BDG patients versus 59% of Fontan patients and survival with favorable neurologic outcome in 22/42 (52%) BDG versus 6/22 (27%) Fontan patients, p = 0.067. Twelve of 24 (50%) BDG and 2/7 (29%) Fontan patients who survived to discharge suffered new morbidity as defined by worsening Functional Status Score. More BDG patients achieved adequate DBP (≥25 mmHg for neonates and infants; ≥ 30 mmHg for children) than Fontan patients (21/23 (91%) vs. 5/11 (46%), p = 0.007). CONCLUSIONS: Only 27% of Fontan patients survived to hospital discharge with favorable neurologic outcome after CPR, likely driven by inadequate diastolic blood pressure during resuscitation. One half of the BDG patients who survived to hospital discharge had new neurologic morbidity. BACKGROUND: Cardiac arrest in patients with congenital heart disease (CHD) may present challenges to resuscitation based on the unique cardiovascular physiology resulting from surgical palliation. Recent resuscitation guidelines for CHD patients highlight the lack of data surrounding these special patient populations.1 Univentricular heart disease is palliated by a series of cardiac surgeries that stepwise result in passive pulmonary perfusion from the systemic venous system directly to the pulmonary vascular bed. The bidirectional Glenn (BDG) palliation directly anastomoses the superior vena cava (SVC) to the pulmonary arterial system and leaves normal inferior vena cava (IVC) venous return to the heart.2 The Fontan palliation baffles IVC flow directly to the pulmonary vascular bed which relieves cyanosis due to right to left shunting, but requires systemic ventricular preload to be directly dependent upon pulmonary vascular resistance and intrathoracic pressures.3 IMPACT STATEMENT: Hemodynamic waveforms from 2 large prospective observational studies now allow for exploration of physiology during cardiopulmonary resuscitation for unique anatomy associated with single ventricle congenital heart disease. Fewer patients with Fontan physiology (46%) achieved an adequate diastolic blood pressure (defined as ≥ 25 mmHg for neonates and infants and ≥ 30 mmHg for children) than bidirectional Glenn patients during cardiopulmonary resuscitation (91%, p = 0.007). Only 27% of Fontan patients survived to hospital discharge with favorable neurologic outcome after cardiopulmonary resuscitation. Of the bidirectional Glenn patients who survived, 50% developed a new morbidity as quantified by the Functional Status Score.

Brief report: incidence and outcomes of pediatric tracheal intubation-associated cardiac arrests in the ICU-RESUS clinical trial.

BACKGROUND: Tracheal intubation (TI)-associated cardiac arrest (TI-CA) occurs in 1.7% of pediatric ICU TIs. Our objective was to evaluate resuscitation characteristics and outcomes between cardiac arrest patients with and without TI-CA. METHODS: Secondary analysis of cardiac arrest patients in both ICU-RESUS trial and ancillary CPR-NOVA study. The primary exposure was TI-CA, defined as cardiac arrest occurred during TI procedure or within 20 min after endotracheal tube placement. The primary outcome was survival to hospital discharge with favorable neurological outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged). RESULTS: Among 315 children with cardiac arrests, 48 (15.2%) met criteria for TI-CA. Pre-existing medical conditions were similar between groups. Pre-arrest non-invasive mechanical ventilation was more common among TI-CA patients (18/48, 37.5%) compared to non-TI-CA patients (35/267, 13.1%). In 48% (23/48), the TI-CA occurred within 20 min after intubation (i.e., not during intubation). Duration of CPR was longer in TI-CA patients (median 11.0 min, interquartile range [IQR]: 2.5, 35.5) than non-TI-CA patients (median 5.0 min, IQR 2.0, 21.0), p = 0.03. Return of spontaneous circulation occurred in 32/48 (66.7%) TI-CA versus 186/267 (69.7%) non-TI-CA, p = 0.73. Survival to hospital discharge with favorable neurological outcome occurred in 29/48 (60.4%) TI-CA versus 146/267 (54.7%) non-TI-CA, p = 0.53. CONCLUSIONS: Fifteen percent of these pediatric ICU cardiac arrests were associated with TI. Half of TI-CA occurred after endotracheal tube placement. While duration of CPR was longer in TI-CA patients, there were no differences in unadjusted outcomes following TI-CA versus non-TI-CA. TRIAL REGISTRATION: The ICU-RESUS (ClinicalTrials.gov Identifier: NCT02837497).

Elevated serum neurologic biomarker profiles after cardiac arrest in a porcine model.

Introduction: Swine exhibit cerebral cortex mitochondrial dysfunction and neuropathologic injury after hypoxic cardiac arrest treated with hemodynamic-directed CPR (HD-CPR) despite normal Cerebral Performance Category scores. We analyzed the temporal evolution of plasma protein biomarkers of brain injury and inflammatory cytokines, as well as cerebral cortical mitochondrial injury and neuropathology for five days following pediatric asphyxia-associated cardiac arrest treated with HD-CPR. Methods: One-month-old swine underwent asphyxia associated cardiac arrest, 10-20 min of HD-CPR (goal SBP 90 mmHg, coronary perfusion pressure 20 mmHg), and randomization to post-ROSC survival duration (24, 48, 72, 96, 120 h; n = 3 per group) with standardized post-resuscitation care. Plasma neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and cytokine levels were collected pre-injury and 1, 6, 24, 48, 72, 96, and 120 h post-ROSC. Cerebral cortical tissue was assessed for: mitochondrial respirometry, mass, and dynamic proteins; oxidative injury; and neuropathology. Results: Relative to pre-arrest baseline (9.4 pg/ml [6.7-12.6]), plasma NfL was increased at all post-ROSC time points. Each sequential NfL measurement through 48 h was greater than the previous value {1 h (12.7 pg/ml [8.4-14.6], p = 0.01), 6 h (30.9 pg/ml [17.7-44.0], p = 0.0004), 24 h (59.4 pg/ml [50.8-96.1], p = 0.0003) and 48 h (85.7 pg/ml [61.9-118.7], p = 0.046)}. Plasma GFAP, inflammatory cytokines or cerebral cortical tissue measurements were not demonstrably different between time points. Conclusions: In a swine model of pediatric cardiac arrest, plasma NfL had an upward trajectory until 48 h post-ROSC after which it remained elevated through five days, suggesting it may be a sensitive marker of neurologic injury following pediatric cardiac arrest.

Risk factors for prolonged infection and secondary infection in pediatric severe sepsis.

PURPOSE: Sepsis causes significant worldwide morbidity and mortality. Inability to clear an infection and secondary infections are known complications in severe sepsis and likely result in worsened outcomes. We sought to characterize risk factors of these complications. METHODS: We performed a secondary analysis of clinical data from 401 subjects enrolled in the PHENOtyping sepsis-induced Multiple organ failure Study. We examined factors associated with prolonged infection, defined as infection that continued to be identified 7 days or more from initial identification, and secondary infection, defined as new infections identified ≥ 3 days from presentation. Multivariable adjustment was performed to examine laboratory markers of immune depression, with immunocompromised and immunocompetent subjects analyzed separately. RESULTS: Illness severity, immunocompromised status, invasive procedures, and site of infection were associated with secondary infection and/or prolonged infection. Persistent lymphopenia, defined as an absolute lymphocyte count (ALC) < 1000 cells/µL twice in the first five days, and persistent neutropenia, defined as absolute neutrophil count (ANC) < 1000 cells/µL twice in the first five days, were associated with secondary and prolonged infections. When adjusted in multivariable analysis, persistent lymphopenia remained associated with secondary infection in both immunocompromised (aOR = 14.19, 95% CI [2.69, 262.22] and immunocompetent subjects (aOR = 2.09, 95% CI [1.03, 4.17]). Persistent neutropenia was independently associated with secondary infection in immunocompromised subjects (aOR = 5.34, 95% CI [1.92, 15.84]). Secondary and prolonged infections were associated with worse outcomes, including death. CONCLUSIONS: Laboratory markers of immune suppression can be used to predict secondary infection. Lymphopenia is an independent risk factor in immunocompromised and immunocompetent patients for secondary infection.

Early bolus epinephrine administration during pediatric cardiopulmonary resuscitation for bradycardia with poor perfusion: an ICU-resuscitation study.

BACKGROUND: Half of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness. METHODS: Prespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016-March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status. RESULTS: Of 452 eligible subjects, 322 (71%) received early epinephrine. The early epinephrine group had higher pre-arrest severity of illness and vasoactive-inotrope scores. Early epinephrine was not associated with survival to discharge (aRR 0.97, 95%CI 0.82, 1.14) or survival with favorable neurologic outcome (aRR 0.99, 95%CI 0.82, 1.18). Among 186 patients with invasive blood pressure waveforms, 118 (63%) had at least 1 period of pulselessness during the first 10 min of CPR; 86 (46%) by 2 min and 100 (54%) by 3 min. Sustained return of spontaneous circulation was highest after bradycardia with poor perfusion (84%) compared to bradycardia with poor perfusion progressing to pulselessness (43%) and bradycardia with poor perfusion progressing to pulselessness followed by return to bradycardia with poor perfusion (62%) (p < 0.001). CONCLUSIONS: In this cohort of pediatric CPR events with an initial rhythm of bradycardia with poor perfusion, we failed to identify an association between early bolus epinephrine and outcomes when controlling for illness severity. Most children receiving CPR for bradycardia with poor perfusion developed subsequent pulselessness, 46% within 2 min of CPR onset.

Characteristics of Pediatric In-Hospital Cardiac Arrests and Resuscitation Duration.

Importance: Cardiopulmonary resuscitation (CPR) duration is associated with cardiac arrest survival. Objectives: To describe characteristics associated with CPR duration among hospitalized children without return of circulation (ROC) (patient-level analysis) and determine whether hospital median CPR duration in patients without ROC is associated with survival (hospital-level analysis). Design, Setting, and Participants: This retrospective cohort study of patients undergoing pediatric in-hospital CPR between January 1, 2000, and December 31, 2021, used data from the Get With the Guidelines-Resuscitation registry. Children receiving chest compressions for at least 2 minutes and/or defibrillation were included in the patient-level analysis. For the hospital-level analysis, sites with at least 20 total events and at least 5 events without ROC were included. Data were analyzed from December 1, 2022, to November 15, 2023. Exposures: For the patient-level analysis, the exposure was CPR duration in patients without ROC. For the hospital-level analysis, the exposure was quartile of median CPR duration in events without ROC at each hospital. Main Outcomes and Measures: For the patient-level analysis, outcomes were patient and event factors, including race and ethnicity and event location; we used a multivariable hierarchical linear regression model to assess factors associated with CPR duration in patients without ROC. For the hospital-level analysis, the main outcome was survival to discharge among all site events; we used a random intercept multivariable hierarchical logistic regression model to examine the association between hospital quartile of CPR duration and survival to discharge. Results: Of 13 899 events, 3859 patients did not have ROC (median age, 7 months [IQR, 0 months to 7 years]; 2175 boys [56%]). Among event nonsurvivors, median CPR duration was longer in those with initial rhythms of bradycardia with poor perfusion (8.37 [95% CI, 5.70-11.03] minutes; P < .001), pulseless electrical activity (8.22 [95% CI, 5.44-11.00] minutes; P < .001), and pulseless ventricular tachycardia (6.17 [95% CI, 0.09-12.26] minutes; P = .047) (vs asystole). Shorter median CPR duration was associated with neonates compared with older children (-4.86 [95% CI, -8.88 to -0.84] minutes; P = .02), emergency department compared with pediatric intensive car7 e unit location (-4.02 [95% CI, -7.48 to -0.57] minutes; P = .02), and members of racial or ethnic minority groups compared with White patients (-3.67 [95% CI, -6.18 to -1.17]; P = .004). Among all CPR events, the adjusted odds of survival to discharge differed based on hospital quartile of median CPR duration among events without ROC; compared with quartile 1 (15.0-25.9 minutes), the adjusted odds ratio for quartile 2 (26.0-29.4 minutes) was 1.22 (95% CI, 1.09-1.36; P < .001); for quartile 3 (29.5-32.9 minutes), 1.23 (95% CI, 1.08-1.39; P = .002); and for quartile 4 (33.0-53.0 minutes), 1.04 (95% CI, 0.91-1.19; P = .58). Conclusions and Relevance: In this retrospective cohort study of pediatric in-hospital CPR, several factors, including age and event location, were associated with CPR duration in event nonsurvivors. The odds of survival to discharge were lower for patients at hospitals with the shortest and longest median CPR durations among events without ROC. Further studies are needed to determine the optimal duration of CPR during pediatric in-hospital cardiac arrest and to provide training guidelines for resuscitation teams to eliminate disparities in resuscitation care.

Association of Postarrest Hypotension Burden With Unfavorable Neurologic Outcome After Pediatric Cardiac Arrest.

OBJECTIVE: Quantify hypotension burden using high-resolution continuous arterial blood pressure (ABP) data and determine its association with outcome after pediatric cardiac arrest. DESIGN: Retrospective observational study. SETTING: Academic PICU. PATIENTS: Children 18 years old or younger admitted with in-of-hospital or out-of-hospital cardiac arrest who had invasive ABP monitoring during postcardiac arrest care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: High-resolution continuous ABP was analyzed up to 24 hours after the return of circulation (ROC). Hypotension burden was the time-normalized integral area between mean arterial pressure (MAP) and fifth percentile MAP for age. The primary outcome was unfavorable neurologic status (pediatric cerebral performance category ≥ 3 with change from baseline) at hospital discharge. Mann-Whitney U tests compared hypotension burden, duration, and magnitude between favorable and unfavorable patients. Multivariable logistic regression determined the association of unfavorable outcomes with hypotension burden, duration, and magnitude at various percentile thresholds from the 5th through 50th percentile for age. Of 140 patients (median age 53 [interquartile range 11-146] mo, 61% male); 63% had unfavorable outcomes. Monitoring duration was 21 (7-24) hours. Using a MAP threshold at the fifth percentile for age, the median hypotension burden was 0.01 (0-0.11) mm Hg-hours per hour, greater for patients with unfavorable compared with favorable outcomes (0 [0-0.02] vs. 0.02 [0-0.27] mm Hg-hr per hour, p < 0.001). Hypotension duration and magnitude were greater for unfavorable compared with favorable patients (0.03 [0-0.77] vs. 0.71 [0-5.01]%, p = 0.003; and 0.16 [0-1.99] vs. 2 [0-4.02] mm Hg, p = 0.001). On logistic regression, a 1-point increase in hypotension burden below the fifth percentile for age (equivalent to 1 mm Hg-hr of burden per hour of recording) was associated with increased odds of unfavorable outcome (adjusted odds ratio [aOR] 14.8; 95% CI, 1.1-200; p = 0.040). At MAP thresholds of 10th-50th percentiles for age, MAP burden below the threshold was greater in unfavorable compared with favorable patients in a dose-dependent manner. CONCLUSIONS: High-resolution continuous ABP data can be used to quantify hypotension burden after pediatric cardiac arrest. The burden, duration, and magnitude of hypotension are associated with unfavorable neurologic outcomes.

Epinephrine Dosing Intervals Are Associated With Pediatric In-Hospital Cardiac Arrest Outcomes: A Multicenter Study.

OBJECTIVES: Data to support epinephrine dosing intervals during cardiopulmonary resuscitation (CPR) are conflicting. The objective of this study was to evaluate the association between epinephrine dosing intervals and outcomes. We hypothesized that dosing intervals less than 3 minutes would be associated with improved neurologic survival compared with greater than or equal to 3 minutes. DESIGN: This study is a secondary analysis of The ICU-RESUScitation Project (NCT028374497), a multicenter trial of a quality improvement bundle of physiology-directed CPR training and post-cardiac arrest debriefing. SETTING: Eighteen PICUs and pediatric cardiac ICUs in the United States. PATIENTS: Subjects were 18 years young or younger and 37 weeks old or older corrected gestational age who had an index cardiac arrest. Patients who received less than two doses of epinephrine, received extracorporeal CPR, or had dosing intervals greater than 8 minutes were excluded. INTERVENTIONS: The primary exposure was an epinephrine dosing interval of less than 3 vs. greater than or equal to 3 minutes. MEASUREMENTS AND MAIN RESULTS: The primary outcome was survival to discharge with a favorable neurologic outcome defined as a Pediatric Cerebral Performance Category score of 1-2 or no change from baseline. Regression models evaluated the association between dosing intervals and: 1) survival outcomes and 2) CPR duration. Among 382 patients meeting inclusion and exclusion criteria, median age was 0.9 years (interquartile range 0.3-7.6 yr) and 45% were female. After adjustment for confounders, dosing intervals less than 3 minutes were not associated with survival with favorable neurologic outcome (adjusted relative risk [aRR], 1.10; 95% CI, 0.84-1.46; p = 0.48) but were associated with improved sustained return of spontaneous circulation (ROSC) (aRR, 1.21; 95% CI, 1.07-1.37; p < 0.01) and shorter CPR duration (adjusted effect estimate, -9.5 min; 95% CI, -14.4 to -4.84 min; p < 0.01). CONCLUSIONS: In patients receiving at least two doses of epinephrine, dosing intervals less than 3 minutes were not associated with neurologic outcome but were associated with sustained ROSC and shorter CPR duration.

Association of EEG characteristics with outcomes following pediatric ICU cardiac arrest: A secondary analysis of the ICU-RESUScitation trial.

BACKGROUND AND OBJECTIVES: There are limited tools available following cardiac arrest to prognosticate neurologic outcomes. Prior retrospective and single center studies have demonstrated early EEG features are associated with neurologic outcome. This study aimed to evaluate the prognostic value of EEG for pediatric in-hospital cardiac arrest (IHCA) in a prospective, multicenter study. METHODS: This cohort study is a secondary analysis of the ICU-Resuscitation trial, a multicenter randomized interventional trial conducted at 18 pediatric and pediatric cardiac ICUs in the United States. Patients who achieved return of circulation (ROC) and had post-ROC EEG monitoring were eligible for inclusion. Patients < 90 days old and those with pre-arrest Pediatric Cerebral Performance Category (PCPC) scores > 3 were excluded. EEG features of interest included EEG Background Category, and presence of focal abnormalities, sleep spindles, variability, reactivity, periodic and rhythmic patterns, and seizures. The primary outcome was survival to hospital discharge with favorable neurologic outcome. Associations between EEG features and outcomes were assessed with multivariable logistic regression. Prediction models with and without EEG Background Category were developed and receiver operator characteristic curves compared. RESULTS: Of the 1129 patients with an index cardiac arrest who achieved ROC in the parent study, 261 had EEG within 24 h of ROC, of which 151 were evaluable. The cohort included 57% males with a median age of 1.1 years (IQR 0.4, 6.8). EEG features including EEG Background Category, sleep spindles, variability, and reactivity were associated with survival with favorable outcome and survival, (all p < 0.001). The addition of EEG Background Category to clinical models including age category, illness category, PRISM score, duration of CPR, first documented rhythm, highest early post-arrest arterial lactate improved the prediction accuracy achieving an AUROC of 0.84 (CI 0.77-0.92), compared to AUROC of 0.76 (CI 0.67-0.85) (p = 0.005) without EEG Background Category. CONCLUSION: This multicenter study demonstrates the value of EEG, in the first 24 h following ROC, for predicting survival with favorable outcome after a pediatric IHCA.

Effect of dimethyl fumarate on mitochondrial metabolism in a pediatric porcine model of asphyxia-induced in-hospital cardiac arrest.

Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage. To investigate the efficacy of DMF in mitigating mitochondrial injury in a pediatric porcine model of IHCA, toddler-aged piglets were subjected to asphyxia-induced CA, followed by ventricular fibrillation, high-quality cardiopulmonary resuscitation, and random assignment to receive either DMF (30 mg/kg) or placebo for four days. Sham animals underwent similar anesthesia protocols without CA. After four days, tissues were analyzed for mitochondrial markers. In the brain, untreated CA animals exhibited a reduced expression of proteins of the oxidative phosphorylation system (CI, CIV, CV) and decreased mitochondrial respiration (p < 0.001). Despite alterations in mitochondrial content and morphology in the myocardium, as assessed per transmission electron microscopy, mitochondrial function was unchanged. DMF treatment counteracted 25% of the proteomic changes induced by CA in the brain, and preserved mitochondrial structure in the myocardium. DMF demonstrates a potential therapeutic benefit in preserving mitochondrial integrity following asphyxia-induced IHCA. Further investigation is warranted to fully elucidate DMF's protective mechanisms and optimize its therapeutic application in post-arrest care.

Establishing correlates of maternal-fetal cytomegalovirus transmission-one step closer through predictive modeling.

BACKGROUND: Determinants of maternal-fetal cytomegalovirus (CMV) transmission and factors influencing the severity of congenital CMV (cCMV) infection are not well understood. METHODS: We conducted a descriptive, multi-center study in pregnant women ≥18 years old with primary CMV infection and their newborns (NCT01251744) to explore maternal immune responses to CMV and determine potential immunologic/virologic correlates of cCMV following primary infection during pregnancy. We developed alternative approaches looking into univariate/multivariate factors associated with cCMV, including a participant clustering/stratification approach and an interpretable predictive model-based approach using trained decision trees for risk prediction (post-hoc analyses). RESULTS: Pregnant women were grouped in three distinct clusters with similar baseline characteristics, particularly gestational age at diagnosis. We observed a trend for higher viral loads in urine and saliva samples from mothers of infants with cCMV versus without cCMV. When using a trained predictive-model approach that accounts for interaction effects between variables, anti-pentamer IgG antibody concentration and viral load in saliva were identified as biomarkers jointly associated with the risk of maternal-fetal CMV transmission. CONCLUSION: We identified biomarkers of CMV maternal-fetal transmission. After validation in larger studies, our findings will guide the management of primary infection during pregnancy and the development of vaccines against cCMV.

The human cytomegalovirus (CMV) is common and usually causes no symptoms in healthy individuals. However, CMV infections can be life-threatening in individuals with improperly functioning or immature immune systems, such as fetuses. Women can become infected with CMV for the first time (primary infection) during pregnancy. If CMV is transmitted from mother to fetus before the second trimester, the infant can suffer from severe disorders such as hearing loss and delayed development. We aimed to identify characteristics of pregnant women with a primary CMV infection that may increase the likelihood of transmitting CMV to the fetus. We considered demographical, clinical, and behavioral characteristics, as well as immune responses and the quantity of virus detected in the women's blood, urine, saliva, and vaginal mucus. Because we could not identify one single characteristic that could predict a high risk of CMV transmission, we developed new data analysis models to study how they can be combined. We found that antibodies targeting a pentameric antigen of the virus envelope and the presence of virus in saliva can together predict the risk of CMV transmission from mother to fetus. Our results can help improve the care of CMV-infected pregnant women and the design of CMV vaccines.

The association of recent simulation training and clinical experience of team leaders with cardiopulmonary resuscitation quality during in-hospital cardiac arrest.

OBJECTIVE: We aimed to investigate the association of recent team leader simulation training (<6 months) and years of clinical experience (≥4 years) with chest compression quality during in-hospital cardiac arrest (IHCA). METHODS: This cohort study of IHCA in four Danish hospitals included cases with data on chest compression quality and team leader characteristics. We assessed the impact of recent simulation training and experienced team leaders on longest chest compression pause duration (primary outcome), chest compression fraction (CCF), and chest compression rates within guideline recommendations using mixed effects models. RESULTS: Of 157 included resuscitation attempts, 45% had a team leader who recently participated in simulation training and 66% had an experienced team leader. The median team leader experience was 7 years [Q1; Q3: 4; 11]. The median duration of the longest chest compression pause was 16 s [10; 30]. Having a team leader with recent simulation training was associated with significantly shorter longest pause durations (difference: -7.11 s (95%-CI: -12.0; -2.2), p = 0.004), a higher CCF (difference: 3% (95%-CI: 2.0; 4.0%), p < 0.001) and with less guideline compliant chest compression rates (odds ratio: 0.4 (95%-CI: 0.19; 0.84), p = 0.02). Having an experienced team leader was not associated with longest pause duration (difference: -1.57 s (95%-CI: -5.34; 2.21), p = 0.42), CCF (difference: 0.7% (95%-CI: -0.3; 1.7), p = 0.17) or chest compression rates within guideline recommendations (odds ratio: 1.55 (95%-CI: 0.91; 2.66), p = 0.11). CONCLUSION: Recent simulation training of team leaders, but not years of team leader experience, was associated with shorter chest compression pauses during IHCA.

Association Between Chest Compression Pause Duration and Survival After Pediatric In-Hospital Cardiac Arrest.

BACKGROUND: The association between chest compression (CC) pause duration and pediatric in-hospital cardiac arrest survival outcomes is unknown. The American Heart Association has recommended minimizing pauses in CC in children to <10 seconds, without supportive evidence. We hypothesized that longer maximum CC pause durations are associated with worse survival and neurological outcomes. METHODS: In this cohort study of index pediatric in-hospital cardiac arrests reported in pediRES-Q (Quality of Pediatric Resuscitation in a Multicenter Collaborative) from July of 2015 through December of 2021, we analyzed the association in 5-second increments of the longest CC pause duration for each event with survival and favorable neurological outcome (Pediatric Cerebral Performance Category ≤3 or no change from baseline). Secondary exposures included having any pause >10 seconds or >20 seconds and number of pauses >10 seconds and >20 seconds per 2 minutes. RESULTS: We identified 562 index in-hospital cardiac arrests (median [Q1, Q3] age 2.9 years [0.6, 10.0], 43% female, 13% shockable rhythm). Median length of the longest CC pause for each event was 29.8 seconds (11.5, 63.1). After adjustment for confounders, each 5-second increment in the longest CC pause duration was associated with a 3% lower relative risk of survival with favorable neurological outcome (adjusted risk ratio, 0.97 [95% CI, 0.95-0.99]; P=0.02). Longest CC pause duration was also associated with survival to hospital discharge (adjusted risk ratio, 0.98 [95% CI, 0.96-0.99]; P=0.01) and return of spontaneous circulation (adjusted risk ratio, 0.93 [95% CI, 0.91-0.94]; P<0.001). Secondary outcomes of any pause >10 seconds or >20 seconds and number of CC pauses >10 seconds and >20 seconds were each significantly associated with adjusted risk ratio of return of spontaneous circulation, but not survival or neurological outcomes. CONCLUSIONS: Each 5-second increment in longest CC pause duration during pediatric in-hospital cardiac arrest was associated with lower chance of survival with favorable neurological outcome, survival to hospital discharge, and return of spontaneous circulation. Any CC pause >10 seconds or >20 seconds and number of pauses >10 seconds and >20 seconds were significantly associated with lower adjusted probability of return of spontaneous circulation, but not survival or neurological outcomes.

Association between survival and number of shocks for pulseless ventricular arrhythmias during pediatric in-hospital cardiac arrest in a national registry.

BACKGROUND: Annually 15,200 children suffer an in-hospital cardiac arrest (IHCA) in the US. Ventricular fibrillation or pulseless ventricular tachycardia (VF/pVT) is the initial rhythm in 10-15% of these arrests. We sought to evaluate the association of number of shocks and early dose escalation with survival for initial VF/pVT in pediatric IHCA. METHODS: Using 2000-2020 data from the American Heart Association's (AHA) Get with the Guidelines®-Resuscitation (GWTG-R) registry, we identified children >48 hours of life and ≤18 years who had an IHCA from initial VF/pVT and received defibrillation. RESULTS: There were 251 subjects (37.7%) who received a single shock and 415 subjects (62.3%) who received multiple shocks. Baseline and cardiac arrest characteristics did not differ between those who received a single shock versus multiple shocks except for duration of arrest and calendar year. The median first shock dose was consistent with AHA dosing recommendations and not different between those who received a single shock versus multiple shocks. Survival was improved for those who received a single shock compared to multiple shocks. However, no difference in survival was noted between those who received 2, 3, or ≥4 shocks. Of those receiving multiple shocks, no difference was observed with early dose escalation. CONCLUSIONS: In pediatric IHCA, most patients with initial VF/pVT require more than one shock. No distinctions in patient or pre-arrest characteristics were identified between those who received a single shock versus multiple shocks. Subjects who received a single shock were more likely to survive to hospital discharge even after adjusting for duration of resuscitation.

Impaired hemodynamics of the patella in patients with patellofemoral pain: A case-control study.

Purpose: According to the homeostasis model, patellofemoral pain (PFP) arises as a consequence of disturbed homeostasis of anterior structures of the knee due to vascular insufficiency. Near-infrared spectroscopy (NIRS) allows to measure changes of concentrations (µmol/cm2) of (de)-oxygenated hemoglobine (HHb and O2Hb). The aim was to study differences in patellar hemodynamics between patients and healthy controls. Methods: Hemodynamics of patients (n = 30 [female = 20, age = 21.5, BMI = 22.9]) and controls (n = 30 (female = 18, age = 21.4, BMI = 22.4]) were evaluated for two activities ('Prolonged Sitting' and 'Stair Descent'). Blinding for health status was implemented. Results: During 'Prolonged Sitting', PFP patients exhibited smaller decreases in mean changes for HHb (PFP [M = -1.5 to -1.9], healthy controls [M = -2.0 to -2.3]) and O2Hb (PFP [M = -2.0 to -3.2], healthy controls [M = -3.4 to -4.1]). However, these differences were statistically non-significant (p = 0.14-0.82 and p = 0.056-0.18, respectively). Conversely, for 'Stair Descent', PFP patients showed statistically significant smaller decreases in mean changes for HHb (PFP [M = -1.9, SD = 1.8], healthy controls [M = -2.5, SD = 1.7], p = 0.043) and O2Hb (PFP [M = -3.2, SD = 3.2], healthy controls [M = -4.9, SD = 2.7], p = 0.004). Conclusions: The differences suggest potential impairment in patellar hemodynamics in PFP patients, providing support for the homeostasis model. Evidence-based treatment strategies targeting patellar hemodynamics should be further refined and subjected to evaluation in clinical trials. Level of Evidence: Level III.

Association of Pediatric Postcardiac Arrest Ventilation and Oxygenation with Survival Outcomes.

Rationale: Adult and pediatric studies provide conflicting data regarding whether post-cardiac arrest hypoxemia, hyperoxemia, hypercapnia, and/or hypocapnia are associated with worse outcomes. Objectives: We sought to determine whether postarrest hypoxemia or postarrest hyperoxemia is associated with lower rates of survival to hospital discharge, compared with postarrest normoxemia, and whether postarrest hypocapnia or hypercapnia is associated with lower rates of survival, compared with postarrest normocapnia. Methods: An embedded prospective observational study during a multicenter interventional cardiopulmonary resuscitation trial was conducted from 2016 to 2021. Patients ⩽18 years old and with a corrected gestational age of ≥37 weeks who received chest compressions for cardiac arrest in one of the 18 intensive care units were included. Exposures during the first 24 hours postarrest were hypoxemia, hyperoxemia, or normoxemia-defined as lowest arterial oxygen tension/pressure (PaO2) <60 mm Hg, highest PaO2 ⩾200 mm Hg, or every PaO2 60-199 mm Hg, respectively-and hypocapnia, hypercapnia, or normocapnia, defined as lowest arterial carbon dioxide tension/pressure (PaCO2) <30 mm Hg, highest PaCO2 ⩾50 mm Hg, or every PaCO2 30-49 mm Hg, respectively. Associations of oxygenation and carbon dioxide group with survival to hospital discharge were assessed using Poisson regression with robust error estimates. Results: The hypoxemia group was less likely to survive to hospital discharge, compared with the normoxemia group (adjusted relative risk [aRR] = 0.71; 95% confidence interval [CI] = 0.58-0.87), whereas survival in the hyperoxemia group did not differ from that in the normoxemia group (aRR = 1.0; 95% CI = 0.87-1.15). The hypercapnia group was less likely to survive to hospital discharge, compared with the normocapnia group (aRR = 0.74; 95% CI = 0.64-0.84), whereas survival in the hypocapnia group did not differ from that in the normocapnia group (aRR = 0.91; 95% CI = 0.74-1.12). Conclusions: Postarrest hypoxemia and hypercapnia were each associated with lower rates of survival to hospital discharge.

Viral DNAemia and DNA Virus Seropositivity and Mortality in Pediatric Sepsis.

Importance: Sepsis is a leading cause of pediatric mortality. Little attention has been paid to the association between viral DNA and mortality in children and adolescents with sepsis. Objective: To assess the association of the presence of viral DNA with sepsis-related mortality in a large multicenter study. Design, Setting, and Participants: This cohort study compares pediatric patients with and without plasma cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), human herpesvirus 6 (HHV-6), parvovirus B19 (B19V), BK polyomavirus (BKPyV), human adenovirus (HAdV), and torque teno virus (TTV) DNAemia detected by quantitative real-time polymerase chain reaction or plasma IgG antibodies to CMV, EBV, HSV-1, or HHV-6. A total of 401 patients younger than 18 years with severe sepsis were enrolled from 9 pediatric intensive care units (PICUs) in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Data were collected from 2015 to 2018. Samples were assayed from 2019 to 2022. Data were analyzed from 2022 to 2023. Main Outcomes and Measures: Death while in the PICU. Results: Among the 401 patients included in the analysis, the median age was 6 (IQR, 1-12) years, and 222 (55.4%) were male. One hundred fifty-four patients (38.4%) were previously healthy, 108 (26.9%) were immunocompromised, and 225 (56.1%) had documented infection(s) at enrollment. Forty-four patients (11.0%) died in the PICU. Viral DNAemia with at least 1 virus (excluding TTV) was detected in 191 patients (47.6%) overall, 63 of 108 patients (58.3%) who were immunocompromised, and 128 of 293 (43.7%) who were not immunocompromised at sepsis onset. After adjustment for age, Pediatric Risk of Mortality score, previously healthy status, and immunocompromised status at sepsis onset, CMV (adjusted odds ratio [AOR], 3.01 [95% CI, 1.36-6.45]; P = .007), HAdV (AOR, 3.50 [95% CI, 1.46-8.09]; P = .006), BKPyV (AOR. 3.02 [95% CI, 1.17-7.34]; P = .02), and HHV-6 (AOR, 2.62 [95% CI, 1.31-5.20]; P = .007) DNAemia were each associated with increased mortality. Two or more viruses were detected in 78 patients (19.5%), with mortality among 12 of 32 (37.5%) who were immunocompromised and 9 of 46 (19.6%) who were not immunocompromised at sepsis onset. Herpesvirus seropositivity was common (HSV-1, 82 of 246 [33.3%]; CMV, 107 of 254 [42.1%]; EBV, 152 of 251 [60.6%]; HHV-6, 253 if 257 [98.4%]). After additional adjustment for receipt of blood products in the PICU, EBV seropositivity was associated with increased mortality (AOR, 6.10 [95% CI, 1.00-118.61]; P = .049). Conclusions and Relevance: The findings of this cohort study suggest that DNAemia for CMV, HAdV, BKPyV, and HHV-6 and EBV seropositivity were independently associated with increased sepsis mortality. Further investigation of the underlying biology of these viral DNA infections in children with sepsis is warranted to determine whether they only reflect mortality risk or contribute to mortality.