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Extracorporeal membrane oxygenation (ECMO) is a high-risk and low-volume life support with increasing clinical study. However, heterogenous outcome definitions impede data assimilation into evidence to guide practice. The Academic Research Consortium (ARC), an international collaborative forum committed to facilitating the creation of stakeholder-driven consensus nomenclature and outcomes for clinical trials of medical devices, supported the ECMO Core Elements Needed for Trials Regulation And quality of Life (ECMO-CENTRAL) ARC. The ECMO-CENTRAL ARC was assembled to develop definitions of paediatric ECMO adverse events for use in clinical trials and regulatory device evaluation. An initial candidate list of ECMO adverse events derived from the mechanical circulatory support ARC was supplemented with a review of ECMO-relevant adverse event definitions collated from literature published between Jan 1, 1988, and Feb 20, 2023. Distinct teams of international topic experts drafted separate adverse event definitions that were harmonised to existing literature when appropriate. Draft definitions were revised for paediatric ECMO relevance with input from patients, families, and an international expert panel of trialists, clinicians, statisticians, biomedical engineers, device developers, and regulatory agencies. ECMO-CENTRAL ARC was revised and disseminated across research societies and professional organisations. Up to three rounds of internet-based anonymous surveys were planned as a modified Delphi process. The expert panel defined 13 adverse event definitions: neurological, bleeding, device malfunction, acute kidney injury, haemolysis, infection, vascular access-associated injury, non-CNS thrombosis, hepatic dysfunction, right heart failure, left ventricular overload, lactic acidaemia, and hypoxaemia. Definitional structure varied. Among 165 expert panel members, 114 were eligible to vote and 111 voted. Consensus was achieved for all proposed definitions. Agreement ranged from 82% to 95%. ECMO-CENTRAL ARC paired rigorous development with methodical stakeholder involvement and dissemination to define paediatric ECMO adverse events. These definitions will facilitate new research and the assimilation of data across clinical trials and ECMO device evaluation in children.

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.

To evaluate the feasibility and potential utility of contrast-enhanced ultrasound for real-time imaging of whole-brain perfusion during cardiopulmonary resuscitation (CPR), cardiac arrest was induced in 8- to 7-week-old 10-kg piglets (Sus scrofa domesticus). Contrast-enhanced ultrasound was performed through a parietal cranial window in the coronal plane visualizing the thalami during hemodynamic-directed CPR. Whole-brain mean and maximum pixel intensities in each slice during resuscitation were calculated. Piglets were monitored for 24 hours postarrest. Seven piglets achieved return of spontaneous circulation and 6 survived to 24 hours. Of the 6 surviving piglets, 2 piglets demonstrated greater intra-CPR brain enhancement at maximum 73.2% and 42.1% and mean 36.7% and 31.9% enhancement above background, respectively, compared with maximum 5.8%, 22.9%, 6.0%, and 26.6% and mean 5.1%, 8.9%, 2.9%, and 6.6% above background, respectively, in the other 4. Intra-CPR average mean arterial pressures were similar between all 6 surviving piglets. One piglet achieved return of spontaneous circulation but expired 10 minutes later with enhancement maximum 45.2% and mean 18.9% enhancement above background. The final piglet did not achieve return of spontaneous circulation and exhibited minimal enhancement at maximum 2.8% and mean 0.9% enhancement above background. Contrast-enhanced ultrasound can detect brain perfusion during CPR, identifying a spectrum of cerebral blood flow responses in the brain despite similar systemic hemodynamics. This novel application can form the basis for future large animal model studies and eventually human clinical studies to further explore the neurologic implications of cerebral blood flow responses during resuscitation and stimulate novel strategies for optimizing brain perfusion restoration.

We explore the correlation of contrast‐enhanced ultrasound (CEUS) parameters to intracranial pressure (ICP) in a porcine experimental model of pediatric cardiac arrest. Eleven pediatric pigs underwent electrically induced cardiac arrest followed by cardiopulmonary resuscitation. ICP was measured using intracranial bolt monitor and CEUS was monitored through a cranial window. Various CEUS parameters were monitored at baseline, immediately post return of spontaneous circulation (ROSC), 1 hour‐post ROSC, and 3 hours post‐ROSC. There was significant ICP correlation with wash‐out slope assessed by CEUS time intensity curve analysis at immediate post‐ROSC. At 3 hours post‐ROSC there was also significant negative correlation between ICP and peak enhancement which may be due to the evolution of anoxic injury. The use of CEUS in assessing disruption of cerebral hemodynamics and ICP post cardiac arrest will need future validation and comparison to other imaging modalities. The correlation between CEUS parameters and ICP may be due to the alterations in cerebral autoregulation that result from anoxic brain injury.

Brain injury remains a leading cause of morbidity and mortality in children. We evaluated the feasibility of using a pediatric swine model to develop contrast-enhanced ultrasound (CEUS)–based measures of brain perfusion for clinical application in various types of brain injury monitoring. Six-week-old, 10-kg swine (N = 10) were anesthetized, and an acoustic window was created in the right frontal cranium to provide visualization of an oblique coronal plane and bilateral thalami. Ultrasound contrast agent was administered via a femoral venous catheter as a weight-based (0.03 mL/kg) bolus. After localization of the imaging plane, CEUS cine clips were acquired for 90 seconds. Bolus injection of contrast agent provided global visualization of cerebral perfusion and highlighted microvasculature in the brain. Preliminary evaluation of bolus kinetics in piglets showed a central gray nuclei–to–cortex ratio similar to human infants with a steep wash-in that crossed and remained above the 1.0 threshold for most of the enhancement period. We demonstrated the similarity in brain perfusion between piglets and human infants, specifically central gray nuclei–to–cortex ratio, showing preliminary feasibility of its use as a pediatric model of brain perfusion. Contrast-enhanced ultrasound can be performed at the bedside as a minimally invasive procedure, and quantitative CEUS may provide critical information regarding changes in brain perfusion as a result of injury or as a response to therapy.

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IMPORTANCE: Pediatric in-hospital cardiac arrest (IHCA) occurs frequently and is associated with high morbidity and mortality. The objective of this narrative review is to summarize the current knowledge and recommendations regarding pediatric IHCA and cardiopulmonary resuscitation (CPR). OBSERVATIONS: Each year, more than 15 000 children receive CPR for cardiac arrest during hospitalization in the United States. As many as 80% to 90% survive the event, but most patients do not survive to hospital discharge. Most IHCAs occur in intensive care units and other monitored settings and are associated with respiratory failure or shock. Bradycardia with poor perfusion is the initial rhythm in half of CPR events, and only about 10% of events have an initial shockable rhythm. Pre–cardiac arrest systems focus on identifying at-risk patients and ensuring that they are in monitored settings. Important components of CPR include high-quality chest compressions, timely defibrillation when indicated, appropriate ventilation and airway management, administration of epinephrine to increase coronary perfusion pressure, and treatment of the underlying cause of cardiac arrest. Extracorporeal CPR and measurement of physiological parameters are evolving areas in improving outcomes. Structured post–cardiac arrest care focused on targeted temperature management, optimization of hemodynamics, and careful intensive care unit management is associated with improved survival and neurological outcomes. CONCLUSIONS AND RELEVANCE: Pediatric IHCA occurs frequently and has a high mortality rate. Early identification of risk, prevention, delivery of high-quality CPR, and post–cardiac arrest care can maximize the chances of achieving favorable outcomes. More research in this field is warranted.

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Objectives:We previously demonstrated cerebral mitochondrial dysfunction in neonatal swine immediately following a period of full-flow cardiopulmonary bypass (CPB). The extent to which this dysfunction persists in the postoperative period and its correlation with other markers of cerebral bioenergetic failure and injury is unknown. We utilized a neonatal swine model to investigate the early evolution of mitochondrial function and cerebral bioenergetic failure after CPB. Methods:Twenty piglets (mean weight 4.4 ± 0.5 kg) underwent 3 h of CPB at 34 °C via cervical cannulation and were followed for 8, 12, 18, or 24 h (n = 5 per group). Markers of brain tissue damage (glycerol) and bioenergetic dysfunction (lactate to pyruvate ratio) were continuously measured in cerebral microdialysate samples. Control animals (n = 3, mean weight 4.1 ± 1.2 kg) did not undergo cannulation or CPB. Brain tissue was extracted immediately after euthanasia to obtain ex-vivo cortical mitochondrial respiration and frequency of cortical microglial nodules (indicative of cerebral microinfarctions) via neuropathology. Results:Both the lactate to pyruvate ratio (P< .0001) and glycerol levels (P= .01) increased in cerebral microdialysate within 8 h after CPB. At 24 h post-CPB, cortical mitochondrial respiration was significantly decreased compared with controls (P= .046). The presence of microglial nodules increased throughout the study period (24 h) (P= .01, R2 = 0.9). Conclusion:CPB results in impaired cerebral bioenergetics that persist for at least 24 h. During this period of bioenergetic impairment, there may be increased susceptibility to secondary injury related to alterations in metabolic delivery or demand, such as hypoglycemia, seizures, and decreased cerebral blood flow.

Acute intravascular hemolysis during extracorporeal membrane oxygenation (ECMO) leads to increased levels of cell-free hemoglobin (FHb). Our aim was to investigate whether FHb levels are associated with nitric oxide (NO) consumption and clinical outcomes. A prospective observational study was performed involving pediatric patients on ECMO. Blood samples were collected before, during, and after the ECMO run, and plasma was evaluated for FHb, oxyhemoglobin, and NO consumption. Clinical data were collected including baseline patient characteristics, indications for ECMO, circuit changes, and mortality. Correlations between laboratory measures and associations between laboratory measures and clinical observations were evaluated. Twenty-three patients (11 male, 17 neonates) were enrolled with a median weight of 3.1 kg (interquartile range, 2.8–14.0 kg) and median ECMO run of 12 days (interquartile range, 5–19 day). There was a significant increase in FHb over time on ECMO (p= .007), and significant correlations were present between NO consumption and both FHb (r= .41, p= .01) and oxyhemoglobin levels (r= .98, p< .0001). Patients on ECMO for sepsis (n = 6) had lower average levels of oxyhemoglobin (mean [standard deviation {SD}] 14.5 [4.4] versus 19.0 [5.0] μM, p= .07) and NO consumption (mean [SD] 15.8 [4.1] versus 19.8 [3.7] μM, p= .04) during ECMO than patients with other indications. In the 3 days leading up to a circuit change, there were increases in mean total cell-free hemoglobin levels (24%/day, p= .08), oxyhemoglobin (37%/day, p= .005), and NO consumption (40%/day, p= .006) (n = 5). There were no significant associations identified between peak or average plasma measures of hemolysis and type of ECMO (venovenous versus venoarterial) or mortality. For children on ECMO, we observed a strong correlation between increased levels of plasma FHb and elevations in oxyhemoglobin and NO consumption; however, these changes were not associated with increased mortality. Increased hemolysis before circuit changes may be both a marker and a contributor to circuit failure.

Approximately 5000 to 10,000 children suffer an in-hospital cardiac arrest requiring cardiopulmonary resuscitation (CPR) each year in the United States. Importantly, 2% to 6% of all children admitted to pediatric intensive care units (ICUs) receive CPR, as do 4% to 6% of children admitted to pediatric cardiac ICUs. Survival from pediatric ICU cardiac arrest has improved substantially during the past 20 years presumably due to improved training methods, CPR quality, and post–resuscitation care. Extracorporeal life support CPR remains an important treatment option for both cardiac and noncardiac ICU patients.

ABSTRACTIntroduction: Pediatric critical illness and associated alterations in organ function can change drug pharmacokinetics (PK). Extracorporeal membrane oxygenation (ECMO), a life-saving therapy for severe cardiac and/or respiratory failure, causes additional PK alterations that affect drug disposition.Areas covered: The purposes of this review are to discuss the PK changes that occur during ECMO, the associated therapeutic implications, and to review PK literature relevant to pediatric ECMO. We discuss various classes of drugs commonly used for pediatric patients on ECMO, including sedatives, analgesics, antimicrobials and cardiovascular drugs. Finally, we discuss future areas of research and recommend strategies for future pediatric ECMO pharmacologic investigations.Expert opinion: Clinicians caring for pediatric patients treated with ECMO must have an understanding of PK alterations that could lead to either therapeutic failures or increased drug toxicity during this life-saving therapy. Limited data currently exist for optimal drug dosing in pediatric populations who are treated with ECMO. While there are clear challenges to conducting and analyzing data associated with clinical pharmacokinetic-pharmacodynamic studies of children on ECMO, we present techniques to address these challenges. Improved understanding of the physiology and drug disposition during ECMO combined with PK-PD modeling will allow for more adaptable and individualized dosing schemes.

Introduction:In preclinical models, hemodynamic-directed CPR (HD-CPR) mitigates post-arrest neurofunctional impairment and cerebral mitochondrial dysfunction. We aimed to explore the temporal evolution of markers of neurologic injury over five days following cardiac arrest treated with HD-CPR.Methods:Pigs (1-month-old) underwent 7min asphyxia, induction of ventricular fibrillation, 10-20min of HD-CPR (goal SBP 90 mmHg, coronary perfusion pressure 20mmHg), randomization to post-ROSC survival duration (24, 48, 72, 96, 120h; n=3 per group) with standardized post-resuscitation care. Plasma neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were collected at 0, 6, 24, 48, 72, 96, 120h and compared by mixed effects analysis. At terminal endpoints, cerebral cortical tissue was assessed for: mitochondrial electron transport system function; citrate synthase quantification (mitochondrial mass); immunoblot quantification of mitochondrial dynamic proteins (Opa-1, MFN-2, DRP-1, FIS-1); ELISA for 4-HNE and protein carbonyls (oxidative injury); and neuropathologic examination for IBA-1 (microglial activation) and GFAP (reactive astrocytes), all compared via ANOVA.Results:All animals had swine cerebral performance category score of 1 (grossly normal) by 24h after injury. Plasma NFL was significantly elevated at 24, 48, 72, 96 (p<0.001) and 120h (p=0.009) compared to baseline. No significant differences were identified between time points for GFAP, mitochondrial measures, or neuropathological outcomes.Discussion:Despite grossly normal neurofunctional status, plasma NFL was elevated from baseline at multiple timepoints. No significant temporal differences were identified in other markers of neurologic injury. NFL may be a sensitive marker of mild neurologic injury post-arrest.

Introduction:Extracorporeal cardiopulmonary resuscitation (ECPR) has been associated with improved outcomes compared to conventional CPR (CCPR) in children with underlying cardiac disease. There are limited data on ECPR survival outcomes in the non-cardiac population.Hypothesis:ECPR will be associated with improved survival to discharge in children without underlying cardiac disease with prolonged CPR.Methods:Retrospective cohort study using the AHA Get With The Guidelines® - Resuscitation registry of children (<18 years) without cardiac disease who received ≥30 minutes of CPR for in-hospital cardiac arrest between 2000-2020. Weighted propensity scores were used to balance ECPR and CCPR groups based 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 was used to estimate the probability of a positive effect from ECPR. A secondary analysis explored temporal trends in ECPR relative to the index year of 2000.Results:Of 875 patients, 159 received ECPR and 716 received CCPR (median age 1 year, primary diagnosis respiratory insufficiency, median CPR duration 45 minutes for full cohort). Survival to discharge was similar between the ECPR group (21.4%) compared to the CCPR group (16.2%) in both the univariable analysis (p= 0.13) and the propensity-weighted multivariable logistic regression (aOR 1.44 [CI 0.85-2.44, p= 0.173]. The Bayesian model estimated an 85.1% probability of a positive effect of ECPR on survival to discharge. ECPR use increased over time (test for trend p<0.001).Conclusion:In children without cardiac disease who required ≥30 minutes of CPR, ECPR usage significantly increased in the last 20 years. Compared to CCPR, ECPR was not associated with a statistically significant increase in survival to discharge. However, a Bayesian model estimated weak evidence of a positive survival effect of ECPR.

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Dysnatremia is common in critically ill children due to disruption of hormonal homeostasis. Children with brain injury are at risk for syndrome of inappropriate antidiuretic hormone, cerebral salt wasting, and sodium losses due to externalized ventricular drain placement. We hypothesized that among PICU patients managed with an externalized ventricular drain, hyponatremia is common, hyponatremia is associated with seizures and in-hospital mortality, and greater sodium fluctuations are associated with in-hospital mortality.

Variables affecting duration of pediatric extracorporeal life support (ECLS) are poorly defined. Prior analyses suggested increased mortality risk with prolonged ECLS. Lung recruitment strategies with improved secretion mobilization may shorten ECLS duration. High frequency percussive ventilation (HFPV) has been used, predominantly in inhalational injury, as a mode of ventilation to improve secretion clearance. We describe the application of HFPV and therapeutic bronchoscopies in pediatric ECLS and evaluate outcomes with a same-center historical control population. After May 2011, all children (n = 14) on ECLS were managed with HFPV during extracorporeal support (HFPV cohort). This group’s demographics and outcomes were compared with ECLS patients in our unit immediately before the utilization of HFPV (pre-HFPV cohort, n = 22). The HFPV and pre-HFPV cohorts had similar demographics and utilization of venoarterial ECLS. In univariate analysis, the HFPV group underwent more bronchoscopies and experienced more ECLS-free days (days alive and off ECLS) at 30 and 60 days. In multivariate analysis, use of HFPV was independently associated with ECLS-free days. We conclude that use of HFPV and bronchoscopies during ECLS for respiratory failure was associated with an increase in ECLS-free days and that this association should be prospectively evaluated.

Children with acute myeloid leukemia are at risk for sepsis and organ failure. Outcomes associated with intensive care support have not been studied in a large pediatric acute myeloid leukemia population. Our objective was to determine hospital mortality of pediatric acute myeloid leukemia patients requiring intensive care.

To determine the prevalence of nonconvulsive seizures in children with abusive head trauma.

In children with respiratory failure secondary to pneumonia, extracorporeal life support can be lifesaving. Our goal was to identify variables associated with mortality in children with pneumonia requiring extracorporeal life support.

To assess the effect of implementation of population-specific postoperative management guidelines on postoperative transfusion in children undergoing cranial vault reconstruction surgery.

Helmet continuous positive applied pressure is a form of noninvasive ventilation (NIV) that has been used to provide respiratory support to COVID-19 patients. Helmet NIV is low-cost, readily available, provides viral filters between the patient and clinician, and may reduce the need for invasive ventilation. Its widespread adoption has been limited, however, by the lack of a respiratory monitoring system needed to address known safety vulnerabilities and to monitor patients. To address these safety and clinical needs, we developed an inexpensive respiratory monitoring system based on readily available components suitable for local manufacture. Open-source design and manufacturing documents are provided. The monitoring system comprises flow, pressure, and CO2 sensors on the expiratory path of the helmet circuit and a central remote station to monitor up to 20 patients. The system is validated in bench tests, in human-subject tests on healthy volunteers, and in experiments that compare respiratory features obtained at the expiratory path to simultaneous ground-truth measurements from proximal sensors. Measurements of flow and pressure at the expiratory path are shown to deviate at high flow rates, and the tidal volumes reported via the expiratory path are systematically underestimated. Helmet monitoring systems exhibit high-flow rate, nonlinear effects from flow and helmet dynamics. These deviations are found to be within a reasonable margin and should, in principle, allow for calibration, correction, and deployment of clinically accurate derived quantities.

BACKGROUND: The concentration of tumor necrosis factor, a proinflammatory cytokine, is increased in the gastrointestinal mucosa of patients with active Crohn's disease (CD) and ulcerative colitis (UC). Neutralization of tumor necrosis factor decreases the mucosal inflammatory response of adults with CD. Little information is available on the use of monoclonal antibody to tumor necrosis factor (infliximab) in children and adolescents with CD or UC.OBJECTIVE: To evaluate the clinical response and side effects of patients to infliximab.METHODS: A retrospective review of data regarding 18 pediatric and adolescent patients with active CD (n = 15) and UC (n = 3) poorly controlled with conventional therapy. All patients received one to six intravenous infusions of infliximab 5 mg/kg, while receiving their usual medications.RESULTS: All patients experienced clinical improvement, including decrease in the frequency of stooling and resolution of extraintestinal symptoms such as arthropathy, malaise, and skin manifestations after treatment with infliximab. All but one patient had a documented decrease in the erythrocyte sedimentation rate. Prednisone dosage was tapered in all but two patients, and discontinued in seven patients. Intravenous infusion of infliximab was well tolerated. One patient developed a rash several days after the infusion. A patient who received six infliximab infusions developed recurrent Staphylococcus aureusinfections, as well as septic arthritis and chronic osteomyelitis during the follow-up period, raising the issue of the long-term safety of infliximab.CONCLUSIONS: Treatment of our patients with refractory CD and UC with infliximab was associated with remarkable clinical improvement. Although the drug may have an important role in their management, further assessment of long-term safety and efficacy is needed.

The molecular pathways underlying hypoxemia-induced alterations in neurodevelopment of infants with congenital heart disease have not been delineated. We used transcriptome analysis to investigate differential gene expression induced by hypoxemia in an ovine artificial-womb model.

Background:This study describes a novel approach to identify diagnostic properties in an electrocardiogram (ECG) waveform to classify cardiac arrest etiologies in human patients. Through an interdependent optimization algorithm linking machine learning and signal processing, the technique allows extensive electrocardiogram analysis, retrieving physiologically relevant and demonstrative characteristics embedded in the waveforms across a population.Methods:Secondary analysis of electrocardiography data collected from swine models of either primary VF (n=17) or secondary asphyxia-associated VF (7 minutes of asphyxia prior to VF induction; n=13). Carrying out the analysis, we develop a mutually related algorithm utilizing wavelet synchrosqueezed transform (WSST) and Machine Learning Tree-Classifier (ML-TC). The extraction of the waveform characteristics (WSST) and the learning stage of the ML algorithm (ML-TC) are mutually related through a genetic optimization method to extract the most effective signal characteristics (and their attributes) with respect to the classification performance. This method thus focuses the WSST analysis on a particular frequency bandwidth of the ECG waveform and previously unknown time-dependent frequency patterns that were consistent across all subjects.Results:The innovative approach uncovers previously unknown frequency patterns in the ECG waveform. The proposed method achieves an average classification accuracy of 100% when using 35-second ECG segments and 93% while using 5-second ECG segments, this being the best results ever obtained for this specific problem.Conclusion:This kind of analytical research demonstrates the benefits of computational intelligence, such as machine learning and optimization. It presents a novel method of viewing frequently used data in electrocardiography and illustrates how new hidden information can be obtained to assist in patient diagnosis and prognosis.