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Objective: To characterize surface-bound proteins and to measure the thickness of fibrin fibers bound to extracorporeal membrane oxygenation (ECMO) circuits used in children., Design: Single-center observational prospective study, April to November 2021., Setting: PICU, Royal Children's Hospital, Melbourne, Australia., Patients: Patients aged less than 18 years on venoarterial ECMO and without preexisting disorder., Interventions: None., Measurements and Main Results: ECMO circuits were collected from six patients. Circuit samples were collected from five different sites, and subsequently processed for proteomic and scanning electron microscopy (SEM) studies. The concentration of proteins bound to ECMO circuit samples was measured using a bicinchoninic acid protein assay, whereas characterization of the bound proteome was performed using data-independent acquisition mass spectrometry. The Reactome Over-representation Pathway Analyses tool was used to identify functional pathways related to bound proteins. For the SEM studies, ECMO circuit samples were prepared and imaged, and the thickness of bound fibrin fibers was measured using the Fiji ImageJ software, version 1.53c ( https://imagej.net/software/fiji/ ). Protein binding to ECMO circuit samples and fibrin networks showed significant intra-circuit and interpatient variation. The median (range) total protein concentration was 19.0 (0-76.9) μg/mL, and the median total number of proteins was 2011 (1435-2777). A total of 933 proteins were commonly bound to ECMO circuit samples from all patients and were functionally involved in 212 pathways, with signal transduction, cell cycle, and metabolism of proteins being the top three pathway categories. The median intra-circuit fibrin fiber thickness was 0.20 (0.15-0.24) μm, whereas the median interpatient fibrin fiber thickness was 0.18 (0.15-0.21) μm., Conclusions: In this report, we have characterized proteins and fiber fibrin thickness bound to ECMO circuits in six children. The techniques and approaches may be useful for investigating interactions between blood, coagulation, and the ECMO circuit and have the potential for circuit design., Competing Interests: Drs. McCafferty and Monagle’s institution received funding from the National Health and Medical Research Council (NHMRC) grant APP1129317. Dr. Attard’s institution received funding from the National Blood Authority, Bayer, and Janssen; he received funding from Anthos; he received support for article research from the NHMRC. Dr. MacLaren reported that he serves on the board of directors of the Extracorporeal Life Support Organization (unpaid). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Nitric oxide (NO) can be safely delivered through the sweep gas to the oxygenator of an extracorporeal membrane oxygenation (ECMO) circuit. It has theoretical benefits such as preventing platelet adhesion to surfaces, mitigating inflammatory response and protection against ischemia-reperfusion injury. In this uncontrolled before-after study of children on ECMO, the outcomes of those who received NO were compared with those who did not. Among 393 ECMO runs (from 337 patients), 192 of 393 (49%) received NO and 201 of 393 (51%) did not. The use of NO was associated with a 37% reduction in circuit change (adjusted risk ratio [aRR]: 0.63, 95% confidence interval [CI]: 0.42-0.93). The aRR (95% CI) for risk of neurologic injury was 0.72 (0.47-1.11). We observed potential heterogeneity of treatment effect for the risk of neurologic injury in children who had cardiac surgery: the risk with NO was lower in those who had cardiac surgery (aRR: 0.50, 95% CI: 0.26-0.96). There was no difference in survival between the study groups. In children managed with NO delivered through the ECMO circuit, we report a reduction in observed rate of circuit change and lower risk of neurologic injury in children who underwent cardiac surgery. Nitric oxide therapy on ECMO warrants prospective evaluation in children., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Background: Extracorporeal membrane oxygenation (ECMO) is used in critically ill children with cardiac and/or respiratory failure. Use is increasing in children with high-risk comorbidities. Reasons children do not survive ECMO are poorly described., Aims: Describe characteristics and cause of death, compare mortality in children with high-risk comorbidities, evaluate mortality trends over a decade., Method: All children <18 years old who received ECMO at this institution from 1 January 2011 to 31 December 2020 were described and categorised by outcome: died on or <48 h post-ECMO, died ≥48 h post-ECMO, survived to hospital discharge. Children who did not survive ECMO (DNSE) were categorised to: ECMO withdrawal for irrecoverable original condition, withdrawal for poor prognosis neurological condition, brain death, withdrawal for poor prognosis with multiple complex conditions, and unsupportable. Poison regression was used to analyse survival trends., Results: Four hundred twenty-eight children received ECMO, 19% DNSE, 14% died ≥48 h post-ECMO and 67% survived. ECMO was electively withdrawn for irrecoverable original condition (39%), poor prognosis for neurological condition (32%) or multiple complex conditions (18%). One hundred twenty-two children had ≥1 high-risk comorbidity. Children with genetic syndromes (58%), risk-adjusted congenital heart surgery score-1 ≥4 (53%), primary immunodeficiency (50%) had lower hospital survival. No children with malignancy/bone marrow transplant survived to hospital discharge. Overall hospital survival was 67%, with no significant change during the study period (P-trend = 0.99)., Conclusion: Children who DNSE have therapy electively withdrawn for irrecoverable disease or poor prognosis. Children with high-risk comorbidities have a reasonable chance of survival. This study informs clinicians ECMO may be a therapeutic option., (© 2024 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Competing Interests: Disclosure: G.M. is the President of the Extracorporeal Life Support Organization (ELSO) (unpaid). The other authors have no conflicts of interest to report. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending royalties.

The continuous contact between blood and the foreign surface of the extracorporeal membrane oxygenation (ECMO) circuit contributes to hemostatic, inflammatory, and other physiological disturbances observed during ECMO. Although previous studies have extensively investigated blood samples from patients on ECMO, cell adsorption to the ECMO circuit as an additional factor that could potentially influence clinical outcomes, has largely been overlooked. Here we provide a detailed immunofluorescence (IF) protocol designed to characterize cellular binding on ECMO circuits collected from patients. Extracorporeal membrane oxygenation circuits were collected from three pediatric patients and an albumin primed-only ECMO circuit was used as control. Circuit samples from five different sites within each ECMO circuit were collected and processed for the IF protocol. CD14 and CD42a antibodies were used to identify platelets and leukocytes bound to each ECMO circuit sample and images captured using inverted fluorescence microscopy. The protocol enables the comprehensive characterization of platelet and leukocyte binding to ECMO circuits collected from patients, which could in turn extend our knowledge of the characteristics of circuit binding and may provide guidance for improved ECMO circuit design., Competing Interests: G.M. is the president of the Extracorporeal Life Support Organization (ELSO). The other authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Objectives: The Gaps in the Congenital Diaphragmatic Hernia (CDH) Journey Priority Setting Partnership (PSP) was developed in collaboration with CDH Australia, James Lind Alliance (JLA) and the Murdoch Children's Research Institute to identify research priorities for people with CDH, their families and healthcare workers in Australasia., Design: Research PSP in accordance with the JLA standardised methodology., Setting: Australian community and institutions caring for patients with CDH and their families., Patients: CDH survivors, families of children born with CDH (including bereaved) and healthcare professionals including critical care physicians and nurses (neonatal and paediatric), obstetric, surgical, allied health professionals (physiotherapists, speech pathologists and speech therapists) and general practitioners., Main Outcome Measure: Top 10 research priorities for CDH., Results: 377 questions, from a community-based online survey, were categorised and collated into 50 research questions. Through a further prioritisation process, 21 questions were then discussed at a prioritisation workshop where they were ranked by 21 participants (CDH survivors, parents of children born with CDH (bereaved and not) and 11 multidisciplinary healthcare professionals) into their top 10 research priorities., Conclusion: Stakeholders' involvement identified the top 10 CDH-related research questions, spanning from antenatal care to long-term functional outcomes, that should be prioritised for future research to maximise meaningful outcomes for people with CDH and their families., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Extracorporeal membrane oxygenation (ECMO) is used in children with cardiopulmonary failure. While the majority of ECMO centers use unfractionated heparin, other anticoagulants, including factor XI and factor XII inhibitors are emerging, which may prove suitable for ECMO patients. However, before these anticoagulants can be applied in these patients, baseline data of FXI and FXII changes need to be acquired., Objectives: This study aimed to describe the longitudinal profile of FXI and FXII antigenic levels and function before, during, and after ECMO in children., Methods: This is a prospective observational study in neonatal and pediatric patients with ECMO (<18 years). All patients with venoarterial ECMO and with sufficient plasma volume collected before ECMO, on day 1 and day 3, and 24 hours postdecannulation were included. Antigenic levels and functional activity of FXI and FXII were determined in these samples. Longitudinal profiles of these values were created using a linear mixed model., Results: Sixteen patients were included in this study. Mean FXI and FXII antigenic levels (U/mL) changed from 7.9 and 53.2 before ECMO to 6.0 and 34.5 on day 3 and they recovered to 8.8 and 39.4, respectively, after stopping ECMO. Function (%) of FXI and FXII decreased from 59.1 and 59.0 to 49.0 and 50.7 on day 3 and recovered to 66.0 and 54.4, respectively., Conclusion: This study provides the first insights into changes of the contact pathway in children undergoing ECMO. FXI and FXII antigen and function change during ECMO. Results from this study can be used as starting point for future contact pathway anticoagulant studies in pediatric patients with ECMO., (© 2023 The Authors.)

Objectives: To investigate changes in von Willebrand factor (VWF) concentration, function, and multimers during pediatric extracorporeal membrane oxygenation (ECMO) and determine whether routine monitoring of VWF during ECMO would be useful in predicting bleeding., Design: Prospective observational study of pediatric ECMO patients from April 2017 to May 2019., Setting: The PICU in a large, tertiary referral pediatric ECMO center., Patients: Twenty-five neonates and children (< 18 yr) supported by venoarterial ECMO., Interventions: None., Measurements and Main Results: Arterial blood samples were collected within 24 hours pre-ECMO, daily for the first 5 days of ECMO, every second day until decannulation, and 24 hours post-ECMO. The STA R Max analyzer was used to measure VWF antigen (VWF:Ag) and ristocetin cofactor (VWF:RCo) activity. VWF collagen binding (VWF:CB) was measured using an enzyme-linked immunosorbent assay. VWF multimers were measured using the semi-automated Hydragel 11 VWF Multimer assay. Corresponding clinical data for each patient was also recorded. A total of 25 venoarterial ECMO patients were recruited (median age, 73 d; interquartile range [IQR], 3 d to 1 yr). The median ECMO duration was 4 days (IQR, 3-8 d) and 15 patients had at least one major bleed during ECMO. The percentage of high molecular weight multimers (HMWM) decreased and intermediate molecular weight multimers increased while patients were on ECMO, irrespective of a bleeding status. VWF:Ag increased and the VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios decreased while patients were on ECMO compared with the baseline pre-ECMO samples and healthy children., Conclusions: Neonates and children on ECMO exhibited a loss of HMWM and lower VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratios compared with healthy children, irrespective of major bleeding occurring. Therefore, monitoring VWF during ECMO would not be useful in predicting bleeding in these patients and changes to other hemostatic factors should be investigated to further understand bleeding during ECMO., Competing Interests: Ms. Van Den Helm’s, Ms. Letunica’s, Mr. McCafferty’s, and Drs. Ignjatovic’s and Monagle’s institutions received funding from the Australian National Health and Medical Research Council. Dr. MacLaren disclosed that he serves on the Board of Directors of the Extracorporeal Life Support Organization. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Empiric vancomycin dosing regimens fail to achieve recommended target trough concentrations of 10-20 mg/L in the majority of infants. This study assessed the performance of a model-based dosing calculator (Vanc App) in achieving target vancomycin concentrations at first steady-state level., Methods: This was a multicenter prospective study in four tertiary pediatric hospitals over an 18-month period. Infants aged 0-90 days with suspected Gram-positive sepsis requiring empiric vancomycin treatment were included if they did not meet any of the exclusion criteria: post-menstrual age (PMA) <25 weeks, weight <500 g, glycopeptide allergy, receiving extracorporeal membrane oxygenation, vancomycin use within the previous 72 h, and renal impairment. The Vanc App used a published population pharmacokinetic model to generate a dose based on the infant's PMA, weight, creatinine, and target vancomycin concentration., Results: A total of 40 infants were included; 40% were female, median (range) weight was 2505 (700-4460) g and median (range) PMA was 37.4 (25.7-49.0) weeks. The median (range) vancomycin dose was 45 (24-79) mg/kg/day. All infants had trough vancomycin concentrations measured at steady-state (24-<48 hours) and 30 (75%) infants achieved target concentrations. Five infants had supratherapeutic (median 25, range 21-38 mg/L) and five had subtherapeutic (median 6, range <5-9 mg/L) concentrations. An area under the concentration-time curve (AUC 0-24 ) of 400-650 mg/L.h was achieved in 33 (83%) infants. There were no infusion-related reactions or nephrotoxicity., Conclusion: Individualized intermittent vancomycin dosing using a model-based online calculator resulted in 75% and 83% of infants achieving target trough and AUC 0-24 , respectively, at first steady-state level. There were no vancomycin-related nephrotoxicity or infusion-related reactions., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Introduction: Hemolysis is a common complication of extracorporeal membrane oxygenation (ECMO). There are few data on whether carboxyhemoglobin (COHb), a potential marker of hemolysis, are elevated during ECMO support., Methods: We conducted a single-center, retrospective study comparing peak COHb levels of children pre-, during, and post-ECMO from January 2017 to August 2020., Results: There were 154 ECMO runs in 147 children (154 PICU admissions) included in the study. The median age was 3.5 (IQR 0.2, 39.2) months. Veno-arterial ECMO was the predominant mode: 146/154 (94.8%). Eighty-seven children (56.5%) underwent cardiac surgery. Peak COHb levels during ECMO were statistically significantly higher compared to pre ECMO (COHb 1.8% (IQR 1.4, 2.6) vs COHb 1.2% (IQR 0.7, 1.7), p < 0.001) and post ECMO (COHb 1.6% (IQR 1.3, 2.2), p = 0.009). Children with COHb ⩾2% were younger and had longer duration of ECMO support. Plasma hemoglobin weakly correlated with COHb level ( r  = 0.14; p = 0.04)., Conclusions: Carboxyhemoglobin levels increased during ECMO support compared to the pre and post ECMO period. Younger age and longer ECMO duration were associated with COHb levels ⩾2%. Plasma hemoglobin weakly correlated with COHb level.

Background: Mortality after repair of total anomalous pulmonary venous drainage (TAPVD) in neonates has remained high. Analysis of risk factors may help identify therapeutic targets to improve survival., Methods: Retrospective analysis of all neonates who underwent simple TAPVD repair., Results: Between 1973 and 2021, 175 neonates underwent TAPVD repair, at a median age of 6 days (interquartile range, 2-15 days) and a mean weight of 3.2 ± 0.6 kg. TAPVD was supracardiac in 42.3% of the patients (74 of 175), cardiac in 14.3% (25 of 175), infracardiac in 40% (70 of 175), and mixed type in 3.4% (6 of 175), with obstruction in 65.7% (115 of 175). Pulmonary hypertension (PHT) crisis occurred in 12% (21 of 175). Early mortality was 9.7% (17 of 175) and late mortality was 5.1% (8 of 158), with most deaths occurring within 1 year (75%; 6 of 8). Survival was 86.5% (95% CI, 80.3%-90.8%) at 1 year and 85.8% (95% CI, 79.6%-90.3%) at 5, 10, 15, and 20 years. Survival was lower in patients with obstructed TAPVD, patients with emergent surgery, and those with PHT crisis. PHT crisis (hazard ratio [HR], 4.93; 95% CI, 1.95-12.51; P  = .001), urgency of surgery (HR, 2.51; 95% CI, 1.11-5.68; P  = .027), and higher pulmonary artery pressure-to-systemic blood pressure percentage ratio (HR, 1.06; 95% CI, 1.01-1.11; P  = .026) were identified as risk factors for mortality. Histopathological analysis of 17 patients (9.7%; 17 of 175) showed signs of pulmonary arterial hypertension with media hypertrophy in 58.8% (10 of 17)., Conclusions: Mortality after TAPVD repair occurred mainly within the first year of life. Urgency of surgery and persistent PHT appears to be risk factors for mortality. Lung biopsy might be useful for identifying patients at risk and guiding newer treatment modalities., (© 2022 The Authors. Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery.)

Background: During hypoxia or acidosis, S-nitrosoglutathione (GSNO) has been shown to protect the cardiomyocyte from ischemia-reperfusion injury. In a randomized double-blinded control study of a porcine model of paediatric cardiopulmonary bypass (CPB), we aimed to evaluate the effects of 2 different doses (low and high) of GSNO., Methods: Pigs weighing 15-20 kg were exposed to CPB with 1 hour of aortic cross-clamp. Prior to and during CPB, animals were randomized to receive low-dose (up to 20 nmol/kg/min) GSNO (n = 8), high-dose (up to 60 nmol/kg/min) GSNO (n = 6), or normal saline (n = 7). Standard cardiac intensive care management was continued for 4 hours post-bypass., Results: There was a reduction in myocyte apoptosis after administration of GSNO (P = .04) with no difference between low- and high-dose GSNO. The low-dose GSNO group had lower pulmonary vascular resistance post-CPB (P = .007). Mitochondrial complex I activity normalized to citrate synthase activity was higher after GSNO compared with control (P = .02), with no difference between low- and high-dose GSNO., Conclusions: In a porcine model of CPB, intravenous administration of GSNO limits myocardial apoptosis through preservation of mitochondrial complex I activity, and improves pulmonary vascular resistance. There appears to be a dose-dependent effect to this protection., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate platelet pathophysiology associated with pediatric extracorporeal membrane oxygenation (ECMO)., Design: Prospective observational study of neonatal and pediatric ECMO patients from September 1, 2016, to December 31, 2019., Setting: The PICU in a large tertiary referral pediatric ECMO center., Patients: Eighty-seven neonates and children (< 18 yr) supported by ECMO., Interventions: None., Measurements and Main Results: Arterial blood samples were collected on days 1, 2, and 5 of ECMO and were analyzed by whole blood flow cytometry. Corresponding clinical data for each patient was also recorded. A total of 87 patients were recruited (median age, 65 d; interquartile range [IQR], 7 d to 4 yr). The median duration of ECMO was 5 days (IQR, 3-8 d) with a median length of stay in PICU and hospital of 18 days (IQR, 10-29 d) and 35 days (IQR, 19-75 d), respectively. Forty-two patients (48%) had at least one major bleed according to a priori determined definitions, and 12 patients (14%) had at least one thrombotic event during ECMO. Platelet fibrinogen receptor expression decreased (median fluorescence intensity [MFI], 29,256 vs 26,544; p = 0.0005), while von Willebrand Factor expression increased (MFI: 7,620 vs 8,829; p = 0.0459) from day 2 to day 5 of ECMO. Platelet response to agonist, Thrombin Receptor Activator Peptide 6, also decreased from day 2 to day 5 of ECMO, as measured by binding with anti-P-selectin, PAC-1 (binds activated GPIIb/IIIa), and anti-CD63 monoclonal antibodies (P-selectin area under the curve [AUC]: 63.46 vs 42.82, respectively, p = 0.0022; PAC-1 AUC: 93.75 vs 74.46, p = 0.0191; CD63 AUC: 55.69 vs 41.76, p = 0.0020)., Conclusions: The loss of platelet response over time may contribute to bleeding during ECMO. These novel insights may be useful in understanding mechanisms of bleeding in pediatric ECMO and monitoring platelet markers clinically could allow for prediction or early detection of bleeding and thrombosis., Competing Interests: Dr. d’Udekem’s institution received funding from Actelion (Janssen) and from Berlin Heart. Drs. Ignjatovic’s and Mongale’s institutions received funding from the National Health and Medical Research Council (grant APP1129317). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Levosimendan use is associated with more successful decannulation from veno-arterial extracorporeal membrane oxygenation (VA ECMO) in adults. We sought to determine the role of levosimendan in children who required VA ECMO after cardiac surgery., Methods: This observational study compares the outcomes of children who required VA ECMO after cardiac surgery and received levosimendan for weaning with those who did not receive the drug. A doubly robust estimation methodology (inverse probability of treatment weighting with regression adjustment) was used to balance study covariates (age, weight, sex, lactate pre-ECMO, vasoactive-inotropic score pre-ECMO, ECMO indication, ECMO modality, Risk Adjustment for Congenital Heart Surgery-1 category), and the final model was further adjusted for duration of ECMO., Results: Between January 2012 and December 2018, 118 eligible children received 145 ECMO runs [failed weaning from cardiopulmonary bypass, 67/145 (46%); low cardiac output state, 30/145 (21%); extracorporeal cardiopulmonary resuscitation, 47/145 (32%); other reasons in 1]. Levosimendan was administered before decannulation in 54/145 (37%) runs. The median time to start levosimendan after ECMO cannulation was 39 h (interquartile range, 14-83 h). The unadjusted rates of weaning failure in the levosimendan vs control group were 7% (4/54) vs 19% (17/91). In the controlled analysis, levosimendan was associated with decreased risk of weaning failure [adjusted relative risk (95% confidence interval), 0.20 (0.07-0.57)] and decreased risk of in-hospital mortality [adjusted relative risk (95% confidence interval), 0.45 (0.26-0.76)]., Conclusions: Levosimendan administration in children requiring VA ECMO after cardiac surgery was associated with decreased risk of weaning failure and decreased in-hospital mortality., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: To examine the effects of patient and treatment variables on circuit lifespan in critically ill children requiring continuous renal replacement therapy., Design: Retrospective observational study based on a prospective registry., Setting: Tertiary referral 30-bed PICU., Patients: One hundred sixty-one critically ill children undergoing continuous renal replacement therapy during an 8-year period (2007-2014) were included in the study., Interventions: Continuous renal replacement therapy., Measurements and Main Results: During the study period, 161 patients received a total of 22,190 hours of continuous renal replacement therapy, with a median duration of 74.75 hours (interquartile range, 32-169.5) per patient. Of the 572 filter circuits used, 276 (48.3%) were changed due to circuit clotting and 262 (45.8%) were electively changed. Median circuit life was 24.62 hours (interquartile range, 10.6-55.3) for all filters and significantly longer for those electively removed as compared to those prematurely removed because of clotting (35.50 hr [interquartile range, 16.9-67.6] vs 22.00 hr [interquartile range, 13.8-42.5]; p < 0.001). Multivariate regression analyses revealed that admission diagnosis (p < 0.001), anticoagulation type (p < 0.001), access type (p = 0.016), and circuit size (p = 0.027) were associated with prolonged circuit life, as well as, in patients on heparin anticoagulation, with higher doses of heparin (p < 0.001) and a prolonged activated partial thromboplastin time (p < 0.001)., Conclusions: In this study, circuit lifespan in pediatric continuous renal replacement therapy was low and appeared to depend upon the patient's diagnosis, the type of access and anticoagulation used as well as the size of the circuit used.

Sepsis and septic shock in newborns causes mortality and morbidity depending on the organism and primary site. ECMO provides cardiorespiratory support to allow adequate organ perfusion during the time for antibiotics and source control surgery (if needed) to occur. ECMO mode and cannulation site vary depending on support required and local preference. Earlier and more aggressive use of ECMO can improve survival., (Copyright © 2020 Butt and Chiletti.)

Background: The surviving sepsis campaign recommends consideration for extracorporeal membrane oxygenation (ECMO) in refractory septic shock. We aimed to define the benefit threshold of ECMO in pediatric septic shock., Methods: Retrospective binational multicenter cohort study of all ICUs contributing to the Australian and New Zealand Paediatric Intensive Care Registry. We included patients < 16 years admitted to ICU with sepsis and septic shock between 2002 and 2016. Sepsis-specific risk-adjusted models to establish ECMO benefit thresholds with mortality as the primary outcome were performed. Models were based on clinical variables available early after admission to ICU. Multivariate analyses were performed to identify predictors of survival in children treated with ECMO., Results: Five thousand sixty-two children with sepsis and septic shock met eligibility criteria, of which 80 (1.6%) were treated with veno-arterial ECMO. A model based on 12 clinical variables predicted mortality with an AUROC of 0.879 (95% CI 0.864-0.895). The benefit threshold was calculated as 47.1% predicted risk of mortality. The observed mortality for children treated with ECMO below the threshold was 41.8% (23 deaths), compared to a predicted mortality of 30.0% as per the baseline model (16.5 deaths; standardized mortality rate 1.40, 95% CI 0.89-2.09). Among patients above the benefit threshold, the observed mortality was 52.0% (13 deaths) compared to 68.2% as per the baseline model (16.5 deaths; standardized mortality rate 0.61, 95% CI 0.39-0.92). Multivariable analyses identified lower lactate, the absence of cardiac arrest prior to ECMO, and the central cannulation (OR 0.31, 95% CI 0.10-0.98, p = 0.046) as significant predictors of survival for those treated with VA-ECMO., Conclusions: This binational study demonstrates that a rapidly available sepsis mortality prediction model can define thresholds for survival benefit in children with septic shock considered for ECMO. Survival on ECMO was associated with central cannulation. Our findings suggest that a fully powered RCT on ECMO in sepsis is unlikely to be feasible.

Aims: Vancomycin is frequently used in critically ill children in whom the drug pharmacokinetics are significantly altered as a result of changes in renal clearance and volume of distribution. Therapeutic drug monitoring (TDM) is recommended to achieve vancomycin trough concentrations between 10 and 20 mg/L. In this study we reviewed vancomycin dosing, TDM and treatment outcomes in paediatric and neonatal intensive care unit patients., Methods: We reviewed the medical records of all patients receiving intravenous vancomycin in a tertiary paediatric and neonatal intensive care unit over a 10-month period. Demographic, vancomycin dosing, TDM and drug-related adverse effects data were collected., Results: In total, 115 children received 126 courses of vancomycin and had at least 1 TDM blood sample taken at steady state. In only 38/126 (30%) courses was the target concentration (10-20 mg/L) achieved at the initial steady state trough sample. Of the 88 courses that had initial trough concentrations outside the target range, the dose was adjusted in only 49 (56%). Overall, minimum doses of 30 mg/kg/day in neonates with a corrected gestational age of <35 weeks, and 50 mg/kg/day in older children, were required to achieve target vancomycin concentrations. Vancomycin-attributable nephrotoxicity occurred in 10/126 (8%) courses and there were no episodes of red man syndrome., Conclusion: In critically ill children, individualised dosing is needed. In the absence of Bayesian model-based dosing, in children with normal renal function, empiric vancomycin doses of at least 30 mg/kg/day in neonates of <35 weeks corrected gestational age, and 50 mg/kg/day in older children, should be considered. Optimisation of TDM practices through the development of protocols, ideally built into electronic medical records, should be considered., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: To identify risk factors associated with mortality in critically ill children requiring continuous renal replacement therapy., Design: Retrospective observational study based on a prospective registry., Setting: Tertiary and quaternary referral 30-bed PICU., Patients: Critically ill children undergoing continuous renal replacement therapy were included in the study., Interventions: Continuous renal replacement therapy., Measurements and Main Results: Overall mortality was 36% (n = 58) among the 161 patients treated with continuous renal replacement therapy during the study period and was significantly higher in patients on extracorporeal membrane oxygenation (47.5%, 28 of 59) than in patients not requiring extracorporeal membrane oxygenation (28.4%, 29 of 102; p = 0.022). According to the admission diagnosis, we found the highest mortality in patients with onco-hematologic disease (77.8%) and the lowest in patients with renal disease (5.6%). Based on multivariate logistic regression analysis, the presence of higher severity of illness score at admission (adjusted odds ratio, 1.49; 95% CI, 1.18-1.89; p < 0.001), onco-hematologic disease (odds ratio, 17.10; 95% CI, 4.10-72.17; p < 0.001), fluid overload 10%-20% (odds ratio, 3.83; 95% CI, 1.33-11.07; p = 0.013), greater than 20% (odds ratio, 15.03; 95% CI, 4.03-56.05; p < 0.001), and timing of initiation of continuous renal replacement therapy (odds ratio, 1.01; 95% CI, 1.00-1.01; p = 0.040) were independently associated with mortality. In our population, the odds of dying increases by 1% for every hour of delay in continuous renal replacement therapy initiation from ICU admission., Conclusions: Mortality in children requiring continuous renal replacement therapy remains high and seems to be related to the underlying disease, the severity of illness, and the degree of fluid overload. In critically ill children at high risk for developing acute kidney injury and fluid overload, earlier initiation of continuous renal replacement therapy might result in decreased mortality.

Background: In 2011 we reported unfavourable outcomes of second-run extracorporeal life support (ECLS) in children. We wanted to investigate whether this previous report affected our strategy and modified our long-term outcomes., Methods: Between 1988 and 2015, 31 patients underwent a second-run ECLS. Median age at the time of first support was 9days (0-16 years). Median length of support for the first and second runs were 4.7days (0.1-10) and 3.6days (0.5-8.7) respectively, with an interval of 1.8days (0.1-66) between supports., Results: There was an increasing trend in the number of patients undergoing second-run ECLS after our report: 21 patients between 1988 and mid-2010 (0.9 patients/year) and 10 between mid-2010 and 2015 (two patients/year) (p=0.06). However, among all the patients who underwent ECLS, the proportion of second-run ECLS was not different before and after 2010 (4% vs. 4.2% respectively, p=0.92). While 58% of patients (18/31) survived weaning of support, only 23% (7/31) survived to hospital discharge and 14% (5/31) were still alive after hospital discharge at a median of 6.5 years (1.2-11.6). The three patients who had positive long-term outcomes had the second-run ECLS instituted to allow for major cardiac operations., Conclusions: Compassionate use of second-run ECLS is difficult to refuse but one should be aware that its outcomes are dismal. In our centre, benefits seem to be limited to cases where the second-run ECLS allows for a major cardiac intervention., (Copyright © 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: In adults, continuous infusions of vancomycin (CIV) are associated with earlier attainment of target drug concentrations, require fewer blood samples for monitoring, and may reduce drug toxicity. We aimed to determine, in young infants, if CIV or intermittent infusions of vancomycin (IIV) better achieves target vancomycin concentrations at the first steady-state level and to compare the frequency of drug-related adverse effects., Methods: In a multicenter randomized controlled trial in 2 tertiary neonatal units over a 40-month period, young infants aged 0 to 90 days requiring vancomycin therapy for at least 48 hours were randomly assigned to CIV and IIV., Results: Of 111 infants randomized, 104 were included in the intention-to-treat analysis. Baseline characteristics were similar for both groups. The proportion of infants achieving target concentrations at the first steady-state level was higher for CIV compared with IIV (45 in 53 [85%] vs 21 in 51 [41%]; P < .001). Fewer dose adjustments were required in the CIV group (median 0; range 0-1) compared with the IIV group (median 1; range 0-3; P < .001). The mean daily dose required to achieve target concentrations was lower with CIV compared with IIV (40.6 [SD 10.7] vs 60.6 [SD 53.0] mg/kg per day, respectively; P = .01). No drug-related adverse effects occurred in either group., Conclusions: In young infants, CIV is associated with earlier and improved attainment of target concentrations compared with IIV. Lower total daily doses are required to achieve target levels with CIV. There is no difference in the rate of drug-related adverse effects., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Objective: To describe the effect of extracorporeal membrane oxygenation (ECMO) on survival and cardiac outcome of neonates with myocardial failure secondary to severe enterovirus (EV) myocarditis., Design: Retrospective case series., Setting: A 15-bed cardiac paediatric intensive care unit (ICU)., Patients: We describe the clinical presentations, cardiac findings, ECMO characteristics and outcome of seven neonates with severe EV myocarditis. Additionally, 35 previously reported cases of EV myocarditis supported with ECMO are presented., Interventions: Extracorporeal membrane oxygenation., Results: Seven neonates presented with cardiovascular collapse within the first 10 days after birth and required ECMO support. Echocardiography showed left ventricular dysfunction in all and additional right ventricular dysfunction in four patients. ECG showing widespread ST changes as well as elevated troponin I indicated myocardial damage. All patients were cannulated onto ECMO shortly after ICU admission. None of the patients suffered cardiac arrest prior to ECMO initiation. Four patients survived ECMO and three survived to hospital discharge. All three survivors showed complete cardiac recovery after a median follow-up of 34 months. The survival rate in 35 previously reported cases was 34% (12/35) and including our seven cases 36% (15/42)., Conclusions: In this case series, ECMO initiation prevented further deterioration and cardiac arrest in neonates with severe EV myocarditis and not responding to conventional medical therapies. Moreover, complete cardiac recovery occurred in survivors. However, these neonates may need long ECMO runs and are at increased risk for mechanical complications. Furthermore, mortality remains high due to greater disease severity., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To characterize the clinical indications, procedural safety, and outcome of critically ill children requiring therapeutic plasma exchange., Design: Retrospective observational study based on a prospective registry., Setting: Tertiary and quaternary referral 30-bed PICU., Patients: Forty-eight critically ill children who received therapeutic plasma exchange during an 8-year period (2007-2014) were included in the study., Interventions: Therapeutic plasma exchange., Measurements and Main Results: A total of 48 patients underwent 244 therapeutic plasma exchange sessions. Of those, therapeutic plasma exchange was performed as sole procedure in 193 (79%), in combination with continuous renal replacement therapy in 40 (16.4%) and additional extracorporeal membrane oxygenation in 11 (4.6%) sessions. The most common admission diagnoses were hematologic disorders (30%), solid organ transplantation (20%), neurologic disorders (20%), and rheumatologic disorders (15%). Complications associated with the procedure occurred in 50 (21.2%) therapeutic plasma exchange sessions. Overall, patient survival from ICU was 82%. Although patients requiring therapeutic plasma exchange alone (n = 31; 64%) had a survival rate of 97%, those with additional continuous renal replacement therapy (n = 13; 27%) and extracorporeal membrane oxygenation (n = 4; 8%) had survival rates of 69% and 50%, respectively. Factors associated with increased mortality were lower Pediatric Index of Mortality 2 score, need for mechanical ventilation, higher number of failed organs, and longer ICU stay., Conclusion: Our results indicate that, in specialized centers, therapeutic plasma exchange can be performed relatively safely in critically ill children, alone or in combination with continuous renal replacement therapy and extracorporeal membrane oxygenation. Outcome in children requiring therapeutic plasma exchange alone is excellent. However, survival decreases with the number of failed organs and the need for continuous renal replacement therapy and extracorporeal membrane oxygenation.

We describe our experience of 30 consecutive children supported with ECMO and receiving 20 ppm of nitric oxide in the oxygenator of the ECMO circuit. Administration of nitric oxide into the ECMO circuit is safe and could potentially mitigate ischaemia reperfusion injury and end-organ dysfunction of children requiring mechanical support.

Kawasaki disease is usually a limited illness of early childhood. However, life-threatening cardiac manifestations can occur, either at acute presentation or as a consequence of coronary arterial involvement. We report the successful use of veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) for cardiac support in two children with Kawasaki disease: one with acute Kawasaki disease shock syndrome, the other with complications of coronary arteritis and subsequent surgery. We also reviewed the reported experience in the ELSO database and available literature.

Objective: Several population-based studies have shown that gestational age 39-40 weeks at birth is associated with superior outcomes in various pediatric settings. A high proportion of births for neonates with congenital heart disease occur before 39 weeks. We aimed to assess the influence of late-term gestation (39-40 wk) on survival in neonates requiring extracorporeal life support following surgery for congenital heart disease., Design: Retrospective cohort study., Setting: The Royal Children's Hospital, Melbourne, Australia., Patients: Neonates requiring extracorporeal life support after cardiac surgery for congenital heart disease., Measurements and Main Results: From 2005 to 2014, 110 neonates (10.5% of neonates undergoing cardiac surgery) required extracorporeal life support after cardiac surgery. Indications were failure to separate from cardiopulmonary bypass in 40 (36%), extracorporeal cardiopulmonary resuscitation in 48 (44%), progressive low cardiac output in 15 (14%), and other reasons in seven (6%). Extracorporeal life support duration was 94 hours (interquartile range, 53-135), and 54 (49%) underwent single ventricle repair. Gestation at birth (n [%]) was as follows: less than 37 weeks, 19 (17%); 37-38 weeks, 38 (35%); 39-40 weeks, 50 (45%); 41 weeks or more, 3 (3%). By multivariable analysis (controlling for age, era of extracorporeal life support 2005-2009 vs 2010-2014, single ventricle status and acute renal failure), gestational age of 39-40 weeks was associated with the lowest odds for intensive care mortality: using less than 37 weeks as referent, the adjusted odds ratio (95% CI) for 37-38 weeks was 0.41 (0.12-1.33); for 39-40 weeks, 0.27 (0.08-0.84); and for 41 weeks or more, 1.06 (0.07-14.7). Similar association was also seen in a subcohort of study neonates (n = 66) who were commenced on extracorporeal life support after admission to intensive care: using less than 37 weeks as referent, the adjusted odds ratio (95% CI) for 37-38 weeks was 0.52 (0.10-2.80) and for 39-40 weeks, 0.15 (0.03-0.81)., Conclusions: In this cohort of neonates requiring extracorporeal life support following cardiac surgery, 39-40 weeks of gestation at birth is associated with the best survival. The additional maturity gained by reaching a gestation of at least 39 weeks is likely to confer a survival advantage in this high-risk cohort.

Objectives: The capacity and limitations of ventricular assist device (VAD) support in single-ventricle physiology remains poorly understood. We aimed to review our experience in the use of VAD support in the single-ventricle circulation to determine its feasibility in this population., Methods: We reviewed our experience with VAD support in patients with single ventricles over the past 25 years. Fifty-seven patients received 64 runs of VAD support between 1990 and 2015 at a median age of 13 days [interquartile range (IQR) 4.1-99.4 days], of which 55 were supported for post-cardiotomy failure. The majority of patients received short-term VAD support, while 4 patients were either directly supported (1) or transitioned onto the Berlin Heart EXCOR (3)., Results: The median duration of support was 3.5 days (IQR 2.8-5.2 days). Twelve patients suffered significant neurological complications, and thromboembolic events occurred in 8 patients. Twenty-nine of the 55 patients were successfully weaned off support (53%). There were 37 inpatient deaths, with a survival-to-hospital discharge rate of 33% (18 of 55). Of the 4 patients supported after early Fontan failure, 3 died. Having a higher mean arterial blood pressure on initiation of VAD support was the only significant predictor of death (hazards ratio 1.08; 95% confidence interval 1.03-1.14; P = 0.002). Patients who required a second run of support had higher hospital mortality (83% vs 63%; P = 0.84). Of the hospital survivors, 12 patients (63%) remain alive without heart transplantation at median 7.2 years (IQR 3.5-14.0) post VAD support., Conclusions: VAD support in patients with a single ventricle has a high hospital mortality, with 1 of 3 patients surviving to discharge. Systemic VAD support is likely futile in the setting of early Fontan failure or when re-initiation of support is required., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

We present the clinical course and management of two infants with idiopathic infantile arterial calcification. Both had coronary artery involvement and presented with ischaemic cardiac failure. Neither responded well to conventional therapy with inotropic agents, glyceryl trinitrate, diuretic and mechanical ventilation, nor to short-term biphosphonates. One was treated with levosimendan and extracorporeal membrane oxygenation to no avail., (© 2010 The Authors. Journal of Paediatrics and Child Health © 2010 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)