Outcomes of Extracorporeal Cardiopulmonary Resuscitation for In-Hospital Cardiac Arrest Among Children With Noncardiac Illness Categories.

OBJECTIVES: The objective of this study was to determine the association of the use of extracorporeal cardiopulmonary resuscitation (ECPR) with survival to hospital discharge in pediatric patients with a noncardiac illness category. A secondary objective was to report on trends in ECPR usage in this population for 20 years. DESIGN: Retrospective multicenter cohort study. SETTING: Hospitals contributing data to the American Heart Association's Get With The Guidelines-Resuscitation registry between 2000 and 2021. PATIENTS: Children (<18 yr) with noncardiac illness category who received greater than or equal to 30 minutes of cardiopulmonary resuscitation (CPR) for in-hospital cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Propensity score weighting balanced ECPR and conventional CPR (CCPR) groups on hospital and patient characteristics. Multivariable logistic regression incorporating these scores tested the association of ECPR with survival to discharge. A Bayesian logistic regression model estimated the probability of a positive effect from ECPR. A secondary analysis explored temporal trends in ECPR utilization. Of 875 patients, 159 received ECPR and 716 received CCPR. The median age was 1.0 [interquartile range: 0.2-7.0] year. Most patients (597/875; 68%) had a primary diagnosis of respiratory insufficiency. Median CPR duration was 45 [35-63] minutes. ECPR use increased over time ( p < 0.001). We did not identify differences in survival to discharge between the ECPR group (21.4%) and the CCPR group (16.2%) in univariable analysis ( p = 0.13) or propensity-weighted multivariable logistic regression (adjusted odds ratio 1.42 [95% CI, 0.84-2.40; p = 0.19]). The Bayesian model estimated an 85.1% posterior probability of a positive effect of ECPR on survival to discharge. CONCLUSIONS: ECPR usage increased substantially for the last 20 years. We failed to identify a significant association between ECPR and survival to hospital discharge, although a post hoc Bayesian analysis suggested a survival benefit (85% posterior probability).

Venovenous Extracorporeal Membrane Oxygenation Initiation for Pediatric Acute Respiratory Distress Syndrome With Cardiovascular Instability is Associated With an Immediate and Sustained Decrease in Vasoactive-Inotropic Scores.

OBJECTIVE: To determine the association of venovenous extracorporeal membrane oxygenation (VV-ECMO) initiation with changes in vasoactive-inotropic scores (VISs) in children with pediatric acute respiratory distress syndrome (PARDS) and cardiovascular instability. DESIGN: Retrospective cohort study. SETTING: Single academic pediatric ECMO center. PATIENTS: Children (1 mo to 18 yr) treated with VV-ECMO (2009-2019) for PARDS with need for vasopressor or inotropic support at ECMO initiation. MEASUREMENTS AND MAIN RESULTS: Arterial blood gas values, VIS, mean airway pressure (mPaw), and oxygen saturation (Sp o2 ) values were recorded hourly relative to the start of ECMO flow for 24 hours pre-VV-ECMO and post-VV-ECMO cannulation. A sharp kink discontinuity regression analysis clustered by patient tested the difference in VISs and regression line slopes immediately surrounding cannulation. Thirty-two patients met inclusion criteria: median age 6.6 years (interquartile range [IQR] 1.5-11.7), 22% immunocompromised, and 75% had pneumonia or sepsis as the cause of PARDS. Pre-ECMO characteristics included: median oxygenation index 45 (IQR 35-58), mPaw 32 cm H 2o (IQR 30-34), 97% on inhaled nitric oxide, and 81% on an advanced mode of ventilation. Median VIS immediately before VV-ECMO cannulation was 13 (IQR 8-25) with an overall increasing VIS trajectory over the hours before cannulation. VISs decreased and the slope of the regression line reversed immediately surrounding the time of cannulation (robust p < 0.0001). There were pre-ECMO to post-ECMO cannulation decreases in mPaw (32 vs 20 cm H 2o , p < 0.001) and arterial P co2 (64.1 vs 50.1 mm Hg, p = 0.007) and increases in arterial pH (7.26 vs 7.38, p = 0.001), arterial base excess (2.5 vs 5.2, p = 0.013), and SpO 2 (91% vs 95%, p = 0.013). CONCLUSIONS: Initiation of VV-ECMO was associated with an immediate and sustained reduction in VIS in PARDS patients with cardiovascular instability. This VIS reduction was associated with decreased mPaw and reduced respiratory and/or metabolic acidosis as well as improved oxygenation.

Neuromonitoring after Pediatric Cardiac Arrest: Cerebral Physiology and Injury Stratification.

BACKGROUND: Significant long-term neurologic disability occurs in survivors of pediatric cardiac arrest, primarily due to hypoxic-ischemic brain injury. Postresuscitation care focuses on preventing secondary injury and the pathophysiologic cascade that leads to neuronal cell death. These injury processes include reperfusion injury, perturbations in cerebral blood flow, disturbed oxygen metabolism, impaired autoregulation, cerebral edema, and hyperthermia. Postresuscitation care also focuses on early injury stratification to allow clinicians to identify patients who could benefit from neuroprotective interventions in clinical trials and enable targeted therapeutics. METHODS: In this review, we provide an overview of postcardiac arrest pathophysiology, explore the role of neuromonitoring in understanding postcardiac arrest cerebral physiology, and summarize the evidence supporting the use of neuromonitoring devices to guide pediatric postcardiac arrest care. We provide an in-depth review of the neuromonitoring modalities that measure cerebral perfusion, oxygenation, and function, as well as neuroimaging, serum biomarkers, and the implications of targeted temperature management. RESULTS: For each modality, we provide an in-depth review of its impact on treatment, its ability to stratify hypoxic-ischemic brain injury severity, and its role in neuroprognostication. CONCLUSION: Potential therapeutic targets and future directions are discussed, with the hope that multimodality monitoring can shift postarrest care from a one-size-fits-all model to an individualized model that uses cerebrovascular physiology to reduce secondary brain injury, increase accuracy of neuroprognostication, and improve outcomes.

Cerebral Autoregulation: A Target for Improving Neurological Outcomes in Extracorporeal Life Support.

Despite improvements in survival after illnesses requiring extracorporeal life support, cerebral injury continues to hinder successful outcomes. Cerebral autoregulation (CA) is an innate protective mechanism that maintains constant cerebral blood flow in the face of varying systemic blood pressure. However, it is impaired in certain disease states and, potentially, following initiation of extracorporeal circulatory support. In this review, we first discuss patient-related factors pertaining to venovenous and venoarterial extracorporeal membrane oxygenation (ECMO) and their potential role in CA impairment. Next, we examine factors intrinsic to ECMO that may affect CA, such as cannulation, changes in pulsatility, the inflammatory and adaptive immune response, intracranial hemorrhage, and ischemic stroke, in addition to ECMO management factors, such as oxygenation, ventilation, flow rates, and blood pressure management. We highlight potential mechanisms that lead to disruption of CA in both pediatric and adult populations, the challenges of measuring CA in these patients, and potential associations with neurological outcome. Altogether, we discuss individualized CA monitoring as a potential target for improving neurological outcomes in extracorporeal life support.

Assessment of Recovery Following Pediatric Traumatic Brain Injury.

OBJECTIVES: We analyzed a prospective database of pediatric traumatic brain injury patients to identify predictors of outcome and describe the change in function over time. We hypothesized that neurologic status at hospital discharge would not reflect the long-term neurologic recovery state. DESIGN: This is a descriptive cohort analysis of a single-center prospective database of pediatric traumatic brain injury patients from 2001 to 2012. Functional outcome was assessed at hospital discharge, and the Glasgow Outcome Scale Extended Pediatrics or Glasgow Outcome Scale was assessed on average at 15.8 months after injury. SETTING: Children's Medical Center Dallas, a single-center PICU and Level 1 Trauma Center. PATIENTS: Patients, 0-17 years old, with complicated-mild/moderate or severe accidental traumatic brain injury. MEASUREMENTS AND MAIN RESULTS: Dichotomized long-term outcome was favorable in 217 of 258 patients (84%), 80 of 82 patients (98%) with complicated-mild/moderate injury and 133 of 172 severe patients (77%). In the bivariate analysis, younger age, motor vehicle collision as a mechanism of injury, intracranial pressure monitor placement, cardiopulmonary resuscitation at scene or emergency department, increased hospital length of stay, increased ventilator days (all with p < 0.01) and occurrence of seizures (p = 0.03) were significantly associated with an unfavorable outcome. In multiple regression analysis, younger age (p = 0.03), motor vehicle collision (p = 0.01), cardiopulmonary resuscitation (p < 0.01), and ventilator days (p < 0.01) remained significant. Remarkably, 28 of 60 children (47%) with an unfavorable Glasgow Outcome Scale at hospital discharge improved to a favorable outcome. In severe patients with an unfavorable outcome at hospital discharge, younger age was identified as a risk factor for remaining in an unfavorable condition (p = 0.1). CONCLUSIONS: Despite a poor neurologic status at hospital discharge, many children after traumatic brain injury will significantly improve at long-term assessment. The factors most associated with outcomes were age, cardiopulmonary resuscitation, motor vehicle collision, intracranial pressure placement, days on a ventilator, hospital length of stay, and seizures. The factor most associated with improvement from an unfavorable neurologic status at discharge was being older.

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.

Pediatric Extracorporeal Cardiopulmonary Resuscitation: Development of a Porcine Model and the Influence of Cardiopulmonary Resuscitation Duration on Brain Injury.

Background The primary objective was to develop a porcine model of prolonged (30 or 60 minutes) pediatric cardiopulmonary resuscitation (CPR) followed by 22- to 24-hour survival with extracorporeal life support, and secondarily to evaluate differences in neurologic injury. Methods and Results Ten-kilogram, 4-week-old female piglets were used. First, model development established the technique (n=8). Then, a pilot study was conducted (n=15). After 80% survival was achieved in the final 5 pilot animals, a proof-of-concept randomized study was completed (n=11). Shams (n=6) underwent anesthesia only. Severe neurological injury was determined by a composite score of mitochondrial function, neuropathology, and cerebral metabolism: scale of 0-6 (severe: >3). Among 15 piglets in the pilot study, overall survival was 10 (67%); of the final 5, overall survival was 4 (80%). Eleven piglets were then randomized to 60 (CPR60, n=5) or 30 minutes of CPR (CPR30, n=5); 1 animal was excluded from prerandomization for intra-abdominal hemorrhage (10/11, 91% survival). Three of 5 animals in the CPR60 group had severe neurological injury scores versus 1 of 5 in the CPR30 group (P=0.52). During ECMO, CPR60 animals had lower pH (CPR60: 7.4 [IQR 7.4-7.4] versus CPR30: 7.5 [IQR 7.4-7.5], P=0.022), higher lactate (CPR60: 6.8 [IQR 6.8-11] versus CPR30: 4.2 [IQR 4.1-4.3] mmol/L; P=0.012), and higher ICP (CPR60: 19.3 [IQR 11.7-29.3] versus CPR30: 7.9 [IQR 6.7-9.3] mm Hg; P=0.037). Both groups had greater mitochondrial injury than shams (CPR60: P<0.001; CPR30: P<0.001). CPR60 did not differ from CPR30 in mitochondrial respiration, neuropathology, or cerebral metabolism. Conclusions A pediatric porcine model of extracorporeal cardiopulmonary resuscitation after 60 and 30 minutes of CPR consistently resulted in 24-hour survival with more severe lactic acidosis in the 60-minute cohort.

Prediction of Return of Spontaneous Circulation in a Pediatric Swine Model of Cardiac Arrest Using Low-Resolution Multimodal Physiological Waveforms.

Monitoring physiological waveforms, specifically hemodynamic variables (e.g., blood pressure waveforms) and end-tidal CO2 (EtCO2), during pediatric cardiopulmonary resuscitation (CPR) has been demonstrated to improve survival rates and outcomes when compared to standard depth-guided CPR. However, waveform guidance has largely been based on thresholds for single parameters and therefore does not leverage all the information contained in multimodal data. We hypothesize that the combination of multimodal physiological features improves the prediction of the return of spontaneous circulation (ROSC), the clinical indicator of short-term CPR success. We used machine learning algorithms to evaluate features extracted from eight low-resolution (4 samples per minute) physiological waveforms to predict ROSC. The waveforms were acquired from the 2nd to 10th minute of CPR in pediatric swine models of cardiac arrest (N = 89, 8-12 kg). The waveforms were divided into segments with increasing length (both forward and backward) for feature extraction, and machine learning algorithms were trained for ROSC prediction. For the full CPR period (2nd to 10th minute), the area under the receiver operating characteristics curve (AUC) was 0.93 (95% CI: 0.87-0.99) for the multivariate model, 0.70 (0.55-0.85) for EtCO2 and 0.80 (0.67-0.93) for coronary perfusion pressure. The best prediction performances were achieved when the period from the 6th to the 10th minute was included. Poor predictions were observed for some individual waveforms, e.g., right atrial pressure. In conclusion, multimodal waveform features carry relevant information for ROSC prediction. Using multimodal waveform features in CPR guidance has the potential to improve resuscitation success and reduce mortality.

A Template for Translational Bioinformatics: Facilitating Multimodal Data Analyses in Preclinical Models of Neurological Injury.

Background: Pediatric neurological injury and disease is a critical public health issue due to increasing rates of survival from primary injuries (e.g., cardiac arrest, traumatic brain injury) and a lack of monitoring technologies and therapeutics for the treatment of secondary neurological injury. Translational, preclinical research facilitates the development of solutions to address this growing issue but is hindered by a lack of available data frameworks and standards for the management, processing, and analysis of multimodal data sets. Methods: Here, we present a generalizable data framework that was implemented for large animal research at the Children's Hospital of Philadelphia to address this technological gap. The presented framework culminates in an interactive dashboard for exploratory analysis and filtered data set download. Results: Compared with existing clinical and preclinical data management solutions, the presented framework accommodates heterogeneous data types (single measure, repeated measures, time series, and imaging), integrates data sets across various experimental models, and facilitates dynamic visualization of integrated data sets. We present a use case of this framework for predictive model development for intra-arrest prediction of cardiopulmonary resuscitation outcome. Conclusions: The described preclinical data framework may serve as a template to aid in data management efforts in other translational research labs that generate heterogeneous data sets and require a dynamic platform that can easily evolve alongside their research.

A randomized and blinded trial of inhaled nitric oxide in a piglet model of pediatric cardiopulmonary resuscitation.

AIM: Inhaled nitric oxide (iNO) during cardiopulmonary resuscitation (CPR) improved systemic hemodynamics and outcomes in a preclinical model of adult in-hospital cardiac arrest (IHCA) and may also have a neuroprotective role following cardiac arrest. The primary objectives of this study were to determine if iNO during CPR would improve cerebral hemodynamics and mitochondrial function in a pediatric model of lipopolysaccharide-induced shock-associated IHCA. METHODS: After lipopolysaccharide infusion and ventricular fibrillation induction, 20 1-month-old piglets received hemodynamic-directed CPR and were randomized to blinded treatment with or without iNO (80 ppm) during and after CPR. Defibrillation attempts began at 10 min with a 20-min maximum CPR duration. Cerebral tissue from animals surviving 1-h post-arrest underwent high-resolution respirometry to evaluate the mitochondrial electron transport system and immunohistochemical analyses to assess neuropathology. RESULTS: During CPR, the iNO group had higher mean aortic pressure (41.6 ±â€¯2.0 vs. 36.0 ±â€¯1.4 mmHg; p = 0.005); diastolic BP (32.4 ±â€¯2.4 vs. 27.1 ±â€¯1.7 mmHg; p = 0.03); cerebral perfusion pressure (25.0 ±â€¯2.6 vs. 19.1 ±â€¯1.8 mmHg; p = 0.02); and cerebral blood flow relative to baseline (rCBF: 243.2 ±â€¯54.1 vs. 115.5 ±â€¯37.2%; p = 0.02). Among the 8/10 survivors in each group, the iNO group had higher mitochondrial Complex I oxidative phosphorylation in the cerebral cortex (3.60 [3.56, 3.99] vs. 3.23 [2.44, 3.46] pmol O2/s mg; p = 0.01) and hippocampus (4.79 [4.35, 5.18] vs. 3.17 [2.75, 4.58] pmol O2/s mg; p = 0.02). There were no other differences in mitochondrial respiration or brain injury between groups. CONCLUSIONS: Treatment with iNO during CPR resulted in superior systemic hemodynamics, rCBF, and cerebral mitochondrial Complex I respiration in this pediatric cardiac arrest model.

The physiologic response to rescue therapy with vasopressin versus epinephrine during experimental pediatric cardiac arrest.

AIM: Compare vasopressin to a second dose of epinephrine as rescue therapy after ineffective initial doses of epinephrine in diverse models of pediatric in-hospital cardiac arrest. METHODS: 67 one- to three-month old female swine (10-30 kg) in six experimental cohorts from one laboratory received hemodynamic-directed CPR, a resuscitation method where high quality chest compressions are provided and vasopressor administration is titrated to coronary perfusion pressure (CoPP) ≥20 mmHg. Vasopressors are given when CoPP is <20 mmHg, in sequences of two doses of 0.02 mg/kg epinephrine separated by minimum one-minute, then a rescue dose of 0.4 U/kg vasopressin followed by minimum two-minutes. Invasive measurements were used to evaluate and compare the hemodynamic and neurologic effects of each vasopressor dose. RESULTS: Increases in CoPP and cerebral blood flow (CBF) were greater with vasopressin rescue than epinephrine rescue (CoPP: +8.16 [4.35, 12.06] mmHg vs. + 5.43 [1.56, 9.82] mmHg, p = 0.02; CBF: +14.58 [-0.05, 38.12] vs. + 0.00 [-0.77, 18.24] perfusion units (PFU), p = 0.005). Twenty animals (30%) failed to achieve CoPP ≥20 mmHg after two doses of epinephrine; 9/20 (45%) non-responders achieved CoPP ≥20 mmHg after vasopressin. Among all animals, the increase in CBF was greater with vasopressin (+14.58 [-0.58, 38.12] vs. 0.00 [-0.77, 18.24] PFU, p = 0.005). CONCLUSIONS: CoPP and CBF rose significantly more after rescue vasopressin than after rescue epinephrine. Importantly, CBF increased after vasopressin rescue, but not after epinephrine rescue. In the 30% that failed to meet CoPP of 20 mmHg after two doses of epinephrine, 45% achieved target CoPP with a single rescue vasopressin dose.