Kerry Johnson

Circuit thrombosis and mechanical failure are important complications during extracorporeal membrane oxygenation (ECMO), but expected circuit duration and predictors of circuit failure remain poorly defined. We performed a retrospective analysis of the Extracorporeal Life Support Organization (ELSO) Registry, including patients aged less than 18 years supported with ECMO between January 2020 and December 2024. Circuit failure was defined as a mechanical complication requiring circuit or component replacement. Time to failure was analyzed using Cox proportional hazards models, and associations with mortality were analyzed using logistic regression and propensity score matching. A total of 20,124 patients with 21,294 runs and 26,318 circuits were included. Circuit failure occurred in 5,052 circuits (19.2%), with at least one replacement in 15.3% of runs. Median time to failure was 129.5 hours (interquartile range [IQR]: 55.0–262.5). Neonatal age, weight less than 3 kg, and higher center volume were associated with increased circuit failure, whereas older age was associated with lower risk. Extracorporeal membrane oxygenation pump flow was not associated with circuit failure. Circuit failure was associated with higher mortality (49.0% vs. 34.1%). In propensity score matching, circuit failure increased absolute mortality risk by 6.1 percentage points ( p < 0.001), with the strongest effect in neonates. Circuit life warrants evaluation as a potential endpoint for future hemocompatibility and anticoagulation studies.

Extracorporeal membrane oxygenation (ECMO) can trigger a systemic inflammatory response syndrome (SIRS) with activation of inflammatory, endothelial, and coagulation system pathways. We assessed in a randomized trial whether a) sweep flow nitric oxide (sNO) reduces these responses, b) what the temporal trajectory of these markers post-ECMO commencement is, and c) how serum marker concentrations are associated with survival. Fifty-three patients were randomized (25 sNO, 28 control). Serum levels of inflammatory cytokines (IL-1, IL-6, IL-8, IL-10, TNF-α), complement (C1q, C3, C4, C5a, C9, factor H, factor B), immune regulators (CD40L, P-Selectin), and coagulation factors (PF4, MBL, ADAMTS13) were measured at (t0) and 1, 12, 24 hours post ( t 1– t 3) ECMO initiation. Sweep flow nitric oxide did not alter serum biomarker trajectories. Across sNO and control groups, serum marker concentrations declined from t 0 to t 1 with variable patterns thereafter, but no consistent ECMO-associated elevation. Elevated IL-6 and IL-8 before and after ECMO commencement were associated with mortality, whereas higher P-Selectin, CD40 Ligand, and PF4 correlated with survival. Sweep flow nitric oxide did not modify markers of inflammation, endothelial, or coagulation activation during ECMO. Evidence of an ECMO-induced cytokine storm was absent, but serum biomarkers predicted mortality in ECMO-supported neonates and children.

Background/Objectives: Conventional cardiopulmonary resuscitation (CCPR) has been the foundational resuscitation approach for decades. Where CCPR is unsuccessful, extracorporeal membrane oxygenation-assisted CPR (ECPR) may improve outcomes. Predicting failure of CCPR and immediate need for ECPR is difficult, and data are lacking. In this retrospective analysis, we analysed both factors that are associated with conversion from CCPR to ECPR and survival outcomes for each event. Methods: Patients having a CPR event that occurred in the PICU between 2016 and 2022 were included. Pre-CPR-event clinical and laboratory data were collected. We recorded whether CPR was converted to ECPR and documented patient outcomes. Results: 201 CPR events occurred in 164 children, with 45 events converted from CCPR to ECPR. Time to ROSC or time to ECMO flow was (median [IQR]) 2 (1.5) min for CCPR events and 37 (21.60) min for ECPR events. The maximum pre-CPR-event lactate values were 1.8 mmol/L for CCPR and 4.5 mmol/L for ECPR events. Respiratory arrest preceded 35.3% of CCPR and 4.4% of ECPR events. PICU mortality was 27.8% for CCPR and 50% for ECPR events. Most deaths occurred because of withdrawal of life-sustaining treatments. In a multivariable analysis, cardiac surgical diagnosis, pre-CPR-event lactate, as well as duration of CPR were associated with conversion from CCPR to ECPR. Conclusions: Our study demonstrates that pre-CPR-event lactate concentrations and duration of arrest should alert clinicians to a high likelihood of needing ECPR, while a preceding respiratory arrest may indicate a low likelihood. Mortality post CCPR is significant, mainly due to overall illness severity rather than the consequences of the CPR event.

Background/Objectives: Conventional cardiopulmonary resuscitation (CCPR) has been the foundational approach to resuscitating children and adults for decades, providing a lifeline through manual chest compressions and ventilatory support. In cases where CCPR is unsuccessful extracorporeal membrane oxygenation assisted CPR (ECPR) may improve outcomes. Predicting in which patients CCPR is unsuccessful and which patients ECPR should be instituted immediately is difficult and data is lacking. In a retrospective analysis we sought to establish which factors are associated with conversion from CCPR to ECPR. Methods: Patients having a CPR-event that occurred in the PICU between January 2016 and December 2022 were included in the study. Pre CPR-event clinical and laboratory data were collected. Conversion from CCPR to ECPR, and patient outcomes were recorded. Results: 201 CPR-events occurred in 164 children. In 45 patients a conversion from CCPR to ECPR occurred. Time to return of spontaneous circulation or time to ECMO flow was (Median; [IQR]) 2; (1,5) and 37 (21,60) min for CCPR and ECPR-events, respectively. The pre CPR-event maximum lactate was 1.8 and 4.5 mmol/L for CCPR and ECPR-events, respectively. PICU mortality was 27.8% in the CCPR and 50% in the ECPR group. Hospital mortality was similar for the CCPR and ECPR group, respectively. Most deaths occurred because of withdrawal of life sustaining treatments. In multivariable analysis cardiac surgical diagnosis, pre CPR-event lactate as well as duration of CPR were associated with conversion of CCPR to ECPR. Conclusions: Our study demonstrates that pre CPR-event lactate concentrations should alert clinicians to a high likelihood of needing ECPR, as should the duration of CPR. Mortality post CCPR is significant, mainly due to overall illness severity, rather than the consequences of the CPR-event.

OBJECTIVES: Pediatric sepsis results in significant morbidity and mortality worldwide. There is an urgent need to investigate adjunctive therapies that can be administered early. We hypothesize that using vitamin C combined with hydrocortisone increases survival free of inotropes/vasopressors support until day 7 compared with standard care. Here we describe the Resuscitation in Paediatric Septic Shock using Vitamin C and Hydrocortisone (RESPOND) trial protocol, which aims to address this hypothesis. DESIGN: Randomized, open label, controlled, parallel-group, three-arm trial with integrated economic evaluation. SETTING: Nine Australia and New Zealand PICUs, with interest from additional international sites. PATIENTS: Children between 7 days and younger than 18 years old who are treated for suspected or confirmed sepsis and receiving inotropes/vasopressors for greater than 1 hour. INTERVENTIONS: IV vitamin C (100 mg/kg [maximum 5 g] every 6 hr) and hydrocortisone (1 mg/kg [maximum 50 mg] every 6 hr), or IV hydrocortisone alone (1 mg/kg [maximum 50 mg] every 6 hr) or standard care. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty-four children will be randomly assigned to receive the interventions, or standard care in a 1:1:1 ratio with stratification by steroid administration pre-randomization and hospital site. The primary outcome is time alive and free of inotropes/vasopressors, censored at 7 days. Secondary outcomes include 28-day mortality, survival free of organ support, PICU length of stay, quality of life, functional status and neurodevelopmental vulnerability at 6 months post-enrollment, and hospitalization-related costs. Statistical analysis will be based on an intention-to-treat principle. The study has ethical approval (HREC/20/QCHQ/69922, dated December 21, 2020), is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12621000247875), commenced recruitment on December 8, 2021, and is expected to finish recruitment by mid-2026. CONCLUSIONS: Dissemination of the results will occur through publication in peer-reviewed journals, presentations at international conferences, and additional consumer-informed pathways.

Aim: Few reports have shown Quality‐of‐Life long‐term outcomes in children with congenital diaphragmatic hernia (CDH) who received extracorporeal membrane oxygenation (ECMO) support. We reviewed the short‐ and long‐term outcomes in CDH patients that were supported with ECMO during their neonatal treatment.Methods: Telephone interviews of parents of CDH children were performed. The Functional Status Scale (FSS) and the Paediatric Quality of Life Inventory (PedQL, Version 4.0) were completed with the parents. All children with a CDH and supported with ECMO from 2010 to 2023 were included in the study.Results: Twenty children were identified, with two having two ECMO runs. Birth weight was 3.2 kg (median). ECMO support lasted for (median) 13.6 days (range 3.8 to 39). Twelve patients were alive at the time of the survey. The age (median) at time of the interview was 6.3 years (range 1 to 12). The FSS score showed no impairment (FSS score 6) in any domain in eight patients. Two patients had a score of 7, and two patients had a score of 8 and 9, respectively. The PedQL showed a median score 84.5, with a physical health summary score of 92.5 and a psychosocial health summary score of 78.7. The cardiac specific PedQL inventory score was 77.Conclusions: ECMO support for CDH patients is associated with functional and Quality of Life outcomes that are similar to that in other PICU discharge populations. Denying ECMO support to CDH patients on the basis of predicted poor long‐term outcomes does not appear to be justified.

Background/Aims: Regulatory guidelines recommend that sponsors develop a risk-based approach to monitoring clinical trials. However, there is a lack of evidence to guide the effective implementation of monitoring activities encompassed in this approach. The aim of this study was to assess the efficiency and impact of the risk-based monitoring approach used for a multicentre randomised controlled trial comparing treatments in paediatric patients undergoing cardiac bypass surgery. Methods: This is a secondary analysis of data from a randomised controlled trial that implemented targeted source data verification as part of the risk-based monitoring approach. Monitoring duration and source to database error rates were calculated across the monitored trial dataset. The monitored and unmonitored trial dataset, and simulated trial datasets with differing degrees of source data verification and cohort sizes were compared for their effect on trial outcomes. Results: In total, 106,749 critical data points across 1,282 participants were verified from source data either remotely or on-site during the trial. The total time spent monitoring was 365 hours, with a median (interquartile range) of 10 (7, 16) minutes per participant. An overall source to database error rate of 3.1% was found, and this did not differ between treatment groups. A low rate of error was found for all outcomes undergoing 100% source data verification, with the exception of two secondary outcomes with error rates >10%. Minimal variation in trial outcomes were found between the unmonitored and monitored datasets. Reduced degrees of source data verification and reduced cohort sizes assessed using simulated trial datasets had minimal impact on trial outcomes. Conclusions: Targeted source data verification of data critical to trial outcomes, which carried with it a substantial time investment, did not have an impact on study outcomes in this trial. This evaluation of the cost-effectiveness of targeted source data verification contributes to the evidence-base regarding the context where reduced emphasis should be placed on source data verification as the foremost monitoring activity.

Background: Extracorporeal membrane oxygenation (ECMO) provides support for the pulmonary or cardiovascular function of children in whom the predicted mortality risk remains very high. The inevitable host inflammatory response and activation of the coagulation cascade due to the extracorporeal circuit contribute to additional morbidity and mortality in these patients. Mixing nitric oxide (NO) into the sweep gas of ECMO circuits may reduce the inflammatory and coagulation cascade activation during ECMO support. Objective: The purpose of this study is to test the feasibility and safety of mixing NO into the sweep gas of ECMO systems and assess its effect on inflammation and coagulation system activation through a pilot randomized controlled trial. Methods: The Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR) trial is an open-label, parallel-group, pilot randomized controlled trial to be conducted at a single center. Fifty patients who require ECMO support will be randomly assigned to receive either NO mixed into the sweep gas of the ECMO system at 20 ppm for the duration of ECMO or standard care (no NO) in a 1:1 ratio, with stratification by support type (veno-venous vs veno-arterial ECMO). Results: Outcome measures will focus on feasibility (recruitment rate and consent rate, and successful inflammatory marker measurements), the safety of the intervention (oxygenation and carbon dioxide control within defined parameters and methemoglobin levels), and proxy markers of efficacy (assessment of cytokines, chemokines, and coagulation factors to assess the impact of NO on host inflammation and coagulation cascade activation, clotting of ECMO components, including computer tomography scanning of oxygenators for clot assessments), bleeding complications, as well as total blood product use. Survival without ECMO and the length of stay in the pediatric intensive care unit (PICU) are clinically relevant efficacy outcomes. Long-term outcomes include neurodevelopmental assessments (Ages and Stages Questionnaire, Strength and Difficulties Questionnaire, and others) and quality of life (Pediatric Quality of Life Inventory and others) measured at 6 and 12 months post ECMO cannulation. Analyses will be conducted on an intention-to-treat basis. Conclusions: The NECTAR study investigates the safety and feasibility of NO as a drug intervention during extracorporeal life support and explores its efficacy. The study will investigate whether morbidity and mortality in patients treated with ECMO can be improved with NO. The intervention targets adverse outcomes in patients who are supported by ECMO and who have high expected mortality and morbidity. The study will be one of the largest randomized controlled trials performed among pediatric patients supported by ECMO. Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12619001518156; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376869 International Registered Report Identifier (IRRID): DERR1-10.2196/43760

BACKGROUND Extracorporeal membrane oxygenation (ECMO) provides support for the pulmonary or cardiovascular function of children in whom the predicted mortality risk remains very high. The inevitable host inflammatory response and activation of the coagulation cascade due to the extracorporeal circuit contribute to additional morbidity and mortality in these patients. Mixing nitric oxide (NO) into the sweep gas of ECMO circuits may reduce the inflammatory and coagulation cascade activation during ECMO support. OBJECTIVE The purpose of this study is to test the feasibility and safety of mixing NO into the sweep gas of ECMO systems and assess its effect on inflammation and coagulation system activation through a pilot randomized controlled trial. METHODS The Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR) trial is an open-label, parallel-group, pilot randomized controlled trial to be conducted at a single center. Fifty patients who require ECMO support will be randomly assigned to receive either NO mixed into the sweep gas of the ECMO system at 20 ppm for the duration of ECMO or standard care (no NO) in a 1:1 ratio, with stratification by support type (veno-venous vs veno-arterial ECMO). RESULTS Outcome measures will focus on feasibility (recruitment rate and consent rate, and successful inflammatory marker measurements), the safety of the intervention (oxygenation and carbon dioxide control within defined parameters and methemoglobin levels), and proxy markers of efficacy (assessment of cytokines, chemokines, and coagulation factors to assess the impact of NO on host inflammation and coagulation cascade activation, clotting of ECMO components, including computer tomography scanning of oxygenators for clot assessments), bleeding complications, as well as total blood product use. Survival without ECMO and the length of stay in the pediatric intensive care unit (PICU) are clinically relevant efficacy outcomes. Long-term outcomes include neurodevelopmental assessments (Ages and Stages Questionnaire, Strength and Difficulties Questionnaire, and others) and quality of life (Pediatric Quality of Life Inventory and others) measured at 6 and 12 months post ECMO cannulation. Analyses will be conducted on an intention-to-treat basis. CONCLUSIONS The NECTAR study investigates the safety and feasibility of NO as a drug intervention during extracorporeal life support and explores its efficacy. The study will investigate whether morbidity and mortality in patients treated with ECMO can be improved with NO. The intervention targets adverse outcomes in patients who are supported by ECMO and who have high expected mortality and morbidity. The study will be one of the largest randomized controlled trials performed among pediatric patients supported by ECMO. CLINICALTRIAL Australian New Zealand Clinical Trials Registry ACTRN12619001518156; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376869 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/43760

In this article, a retrospective study was performed to describe the impact of merging two pediatric intensive care units on the overall and neurocognitive outcomes of children who required extracorporeal cardiopulmonary resuscitation (ECPR). Results from three cohorts were compared: 2008 to 2014: premerge, 2014 to 2017: initial time period postmerge, and 2018 to 2019: established merge. Survival to hospital discharge (and with good neurological outcome) was of 68% (61%), 46% (36%), and 79% (71%), respectively, for the three time periods. Merging two hospitals resulted in a nonsignificant trend toward temporary worse outcomes in pediatric patients requiring ECPR.