Outcomes of Extracorporeal Life Support in Children with Meningococcal Septicemia: A Retrospective Cohort Study.

Meningococcal disease is associated with high mortality despite aggressive antibiotic therapy and intensive care support. Patients may develop refractory hypotension and acute respiratory distress syndrome in which extracorporeal membrane oxygenation (ECMO) could serve as a life-saving rescue therapy. However, there is limited data regarding the outcomes of ECMO support in the setting of meningococcal disease. This retrospective analysis of prospectively collected data from Extracorporeal Life Support Organization registry (1989-2019) enrolled children (29 days-18 years old) with Neisseria meningitidis infection receiving ECMO for any support type and mode. A total of 122 patients underwent a single course of ECMO support, equating to 122 ECMO runs. The overall survival-to-discharge rate was 46.7%. Patients receiving pulmonary venovenous (VV) ECMO had the highest survival-to-discharge of 85.7%, while those receiving venoarterial (VA) ECMO for pulmonary indications had a survival of 32.4%. Patients receiving VA ECMO support for cardiac indications had a survival-to-discharge rate of 60.9%. Those needing extracorporeal cardiopulmonary resuscitation (ECPR) had a poor survival (14.3%). Hemorrhagic complications were common, occurring in 43.4% of patients, but not found to be associated with mortality (complication was present in 47.7% of deceased and 38.6% of survivors, p = 0.31). Multivariable logistic regression analysis revealed that neurologic complications were associated with increased odds of mortality (odds ratio: 44.11; 95% confidence interval: 4.95-393.08). ECMO can be utilized as rescue therapy in children with refractory cardiopulmonary failure in setting of meningococcemia. Patients who require pulmonary VV or cardiac ECMO have the best ECMO outcomes. However, the use of ECMO in those suffering cardiac arrest (ECPR) should be undertaken with caution.

Unplanned Extubation During Pediatric Cardiac Intensive Care: U.S. Multicenter Registry Study of Prevalence and Outcomes.

OBJECTIVES: The epidemiology of unplanned extubations (UEs) and associated adverse outcomes in pediatric cardiac ICUs (CICU). DESIGN: Registry data (August 2014 to October 2020). SETTING: Forty-five Pediatric Cardiac Critical Care Consortium hospitals. PATIENTS: Patients receiving mechanical ventilation (MV) via endotracheal tube (ETT). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fifty-six thousand five hundred eight MV courses occurred in 36,696 patients, with a crude UE rate of 2.8%. In cardiac surgical patients, UE was associated with longer duration of MV, but we failed to find such association in medical patients. In both cohorts, UE was associated with younger age, being underweight, and airway anomaly. In multivariable logistic regression, airway anomaly was associated with UE in all patients. Younger age, higher Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery score category, longer duration of MV, and initial oral rather than nasal ETT are associated with UE in the surgical group, but we failed to find such associations in the medical group. UE was associated with a higher reintubation rate compared with elective extubation (26.8 vs 4.8%; odds ratio [OR], 7.35; 95% CI, 6.44-8.39; p < 0.0001) within 1 day of event. After excluding patients having redirection of care, UE was associated with at least three-fold greater odds for each of ventilator-associated pneumonia (VAP), cardiac arrest, and use of mechanical circulatory support (MCS). However, we failed to identify an association between UE and greater odds of mortality (1.2 vs 0.8%; OR, 1.48; 95% CI, 0.86-2.54; p = 0.15), but uncertainty remains. CONCLUSIONS: UE in CICU patients is associated with greater odds of cardiac arrest, VAP, and MCS. Cardiac medical and surgical patients in the CICU appear to have different explanatory factors associated with UE, and perhaps these may be modifiable and tested in future collaborative population research.

Implementation of a 24-hour infection diagnosis protocol in the pediatric cardiac intensive care unit (CICU).

OBJECTIVES: To reduce unnecessary antibiotic exposure in a pediatric cardiac intensive care unit (CICU). DESIGN: Single-center, quality improvement initiative. Monthly antibiotic utilization rates were compared between 12-month baseline and 18-month intervention periods. SETTING: A 25-bed pediatric CICU. PATIENTS: Clinically stable patients undergoing infection diagnosis were included. Patients with immunodeficiency, mechanical circulatory support, open sternum, and recent culture-positive infection were excluded. INTERVENTIONS: The key drivers for improvement were standardizing the infection diagnosis process, order-set creation, limitation of initial antibiotic prescription to 24 hours, discouraging indiscriminate vancomycin use, and improving bedside communication and situational awareness regarding the infection diagnosis protocol. RESULTS: In total, 109 patients received the protocol; antibiotics were discontinued in 24 hours in 72 cases (66%). The most common reasons for continuing antibiotics beyond 24 hours were positive culture (n = 13) and provider preference (n = 13). A statistical process control analysis showed only a trend in monthly mean antibiotic utilization rate in the intervention period compared to the baseline period: 32.6% (SD, 6.1%) antibiotic utilization rate during the intervention period versus 36.6% (SD, 5.4%) during the baseline period (mean difference, 4%; 95% CI, -0.5% to -8.5%; P = .07). However, a special-cause variation represented a 26% reduction in mean monthly vancomycin use during the intervention period. In the patients who had antibiotics discontinued at 24 hours, delayed culture positivity was rare. CONCLUSIONS: Implementation of a protocol limiting empiric antibiotic courses to 24 hours in clinically stable, standard-risk, pediatric CICU patients with negative cultures is feasible. This practice appears safe and may reduce harm by decreasing unnecessary antibiotic exposure.

Extracorporeal Membrane Oxygenation in Congenital Heart Disease.

Mechanical circulatory support (MCS) is a key therapy in the management of patients with severe cardiac disease or respiratory failure. There are two major forms of MCS commonly employed in the pediatric population-extracorporeal membrane oxygenation (ECMO) and ventricular assist device (VAD). These modalities have overlapping but distinct roles in the management of pediatric patients with severe cardiopulmonary compromise. The use of ECMO to provide circulatory support arose from the development of the first membrane oxygenator by George Clowes in 1957, and subsequent incorporation into pediatric cardiopulmonary bypass (CPB) by Dorson and colleagues. The first successful application of ECMO in children with congenital heart disease undergoing cardiac surgery was reported by Baffes et al. in 1970. For the ensuing nearly two decades, ECMO was performed sparingly and only in specialized centers with varying degrees of success. The formation of the Extracorporeal Life Support Organization (ELSO) in 1989 allowed for the collation of ECMO-related data across multiple centers for the first time. This facilitated development of consensus guidelines for the use of ECMO in various populations. Coupled with improving ECMO technology, these advances resulted in significant improvements in ECMO utilization, morbidity, and mortality. This article will review the use of ECMO in children with congenital heart disease.

Acute Kidney Injury and Fluid Overload in Pediatric Extracorporeal Cardio-Pulmonary Resuscitation: A Multicenter Retrospective Cohort Study.

Acute kidney injury (AKI) and fluid overload (FO) are common complications of extracorporeal membrane oxygenation (ECMO). The purpose of this study was to characterize AKI and FO in children receiving extracorporeal cardiopulmonary resuscitation (eCPR). We performed a multicenter retrospective study of children who received eCPR. AKI was assessed during ECMO and FO defined as <10% [FO-] vs. ≥10% [FO+] evaluated at ECMO initiation and discontinuation. A composite exposure, defined by a four-group discrete phenotypic classification [FO-/AKI-, FO-/AKI+, FO+/AKI-, FO+/AKI+] was also evaluated. Primary outcome was mortality and hospital length of stay (LOS) among survivors. 131 patients (median age 29 days (IQR:9, 242 days); 51% men and 82% with underlying cardiac disease) were included. 45.8% survived hospital discharge. FO+ at ECMO discontinuation, but not AKI was associated with mortality [aOR=2.3; 95% CI: 1.07-4.91]. LOS for FO+ patients was twice as long as FO- patients, irrespective of AKI status [(FO+/AKI+ (60 days; IQR: 49-83) vs. FO-/AKI+ (30 days, IQR: 19-48 days); P = 0.01]. FO+ at ECMO initiation and discontinuation was associated with an adjusted 66% and 50% longer length of stay respectively. Prospective studies that target timing and strategy of fluid management, including its removal in children receiving ECPR are greatly needed.

Outcomes of Multiple Runs of Extracorporeal Membrane Oxygenation: An analysis of the Extracorporeal Life Support Registry.

OBJECTIVE: When patients deteriorate after decannulation from extracorporeal membrane oxygenation (ECMO), a second run of extracorporeal support may be considered. However, repeat cannulation can be difficult and poor outcomes associated with multiple ECMO runs are a concern. The aim of this study was to evaluate outcomes and identify factors associated with survival and mortality in cases of multiple runs of extracorporeal membrane oxygenation. DESIGN: Retrospective cohort analysis of the Extracorporeal Life Support Organization Registry. SETTING: The Extracorporeal Life Support Organization's registry was queried for neonates, children, and adults receiving 2 or more runs of ECMO during the same hospitalization, for any indication, from 1998 to 2015. PATIENTS: 1,818 patients from the Extracorporeal Life Support Organization Registry. RESULTS: Of the 1,818 patients, 1,648 underwent 2 runs and 170 underwent 3 or more runs of ECMO. The survival to discharge rate was 36.7% for 2 runs and 29.4% for 3 or more runs. No significant differences in survival were detected in analysis by decade of ECMO run (p = 0.21). Pediatric patients had less mortality than adults (OR: 0.45, 95%CI: 0.24-0.82). Cardiac support on the first run portrayed worse mortality than pulmonary support regardless of final run indication (OR:1.38, 95%CI: 1.09-1.75). Across all age groups, patients receiving pulmonary support on the last run tended to have higher survival rates regardless of support type on the first run. The only first run complication independently predictive of mortality on the final run was renal complications (OR: 1.60, 95%CI: 1.28-1.99). CONCLUSIONS: Though the use of multiple runs of ECMO is growing, outcomes remain poor for most cohorts. Survival decreases with each additional run. Patients requiring additional runs for a pulmonary indication should be considered prime candidates. Renal complications on the first run significantly increases the risk of mortality on subsequent runs, and as such, careful consideration should be applied in these cases.

Outcomes of Single-Ventricle Patients Supported With Extracorporeal Membrane Oxygenation.

OBJECTIVES: Extracorporeal membrane oxygenation is often used in children with single-ventricle anomalies. We aimed to describe extracorporeal membrane oxygenation use in single-ventricle patients to test the hypothesis that despite increasing prevalence, mortality has not improved and overall burden measure by hospital charges and length of stay have increased. DESIGN: Retrospective analysis of the Healthcare Cost and Utilization Project Kids' Inpatient Database was performed with sample weighting to generate national estimates. PATIENTS: Pediatric patients (age ≤ 20) with a diagnosis of single ventricle heart disease requiring extracorporeal membrane oxygenation support from 2000 to 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Seven hundred one children (95% CI, 559-943) with single ventricle were supported with extracorporeal membrane oxygenation in the reporting period. Mortality was 57% and did not improve over time (2000 = 52%, 2003 = 63%, 2006 = 57%, and 2009 = 55%; p = 0.66). Single-ventricle patients who required extracorporeal membrane oxygenation were more likely to have had a cardiac procedure (90% vs 46%; p < 0.001), a diagnosis of arrhythmia (22% vs 13%; p < 0.001), cerebrovascular or neurologic insult (9% vs 1%; p < 0.001), heart failure (24% vs 12%; p < 0.001), acute renal failure (28% vs 3%; p < 0.001), or sepsis (28% vs 8%; p < 0.001). By multivariable analysis, acute renal failure was a risk factor for mortality (adjusted odds ratio, 3.12; 95% CI, 1.95-4.98; p < 0.001). The length of stay for single-ventricle patients with extracorporeal membrane oxygenation increased from 25.2 days in 2000 to 55.6 days in 2009 (p < 0.001). Total inflation-adjusted charges increased from $358,021 (95% CI, $278,658-439,765) in 2000 to $732,349 (95% CI, $671,781-792,917) in 2009 (p < 0.001). CONCLUSIONS: Extracorporeal membrane oxygenation support is uncommon with single-ventricle admissions occurring in 2.3% of all hospitalizations. Among those patients, the mortality rate was 57% with no change over time. Acute renal failure was an independent risk factor for mortality during hospitalization. In addition, length of stay for these patients increased and hospital charges doubled. Further studies are needed to determine suitability and cost-effectiveness of extracorporeal membrane oxygenation in single-ventricle patients.

BMP-2 and TGFß2 shared pathways regulate endocardial cell transformation.

Valvular heart disease is a major cause of mortality and morbidity. Revealing the cellular processes and molecules that regulate valve formation and remodeling is required to develop effective therapies. A key step in valve formation during heart development is the epithelial-mesenchymal transformation (EMT) of a subpopulation of endocardial cells in the atrioventricular cushion (AVC). The type III transforming growth factor-ß receptor (TGFßR3) regulates AVC endocardial cell EMT in vitro and mesenchymal cell differentiation in vivo. Little is known concerning the signaling mechanisms downstream of TGFßR3. Here we use endocardial cell EMT in vitro to determine the role of 2 well-characterized downstream TGFß signaling pathways in TGFßR3-dependent endocardial cell EMT. Targeting of Smad4, the common mediator Smad, demonstrated that Smad signaling is required for EMT in the AVC and TGFßR3-dependent EMT stimulated by TGFß2 or BMP-2. Although we show that Smads 1, 2, 3, and 5 are required for AVC EMT, overexpression of Smad1 or Smad3 is not sufficient to induce EMT. Consistent with the activation of the Par6/Smurf1 pathway downstream of TGFßR3, targeting ALK5, Par6, or Smurf1 significantly inhibited EMT in response to either TGFß2 or BMP-2. The requirement for ALK5 activity, Par6, and Smurf1 for TGFßR3-dependent endocardial cell EMT is consistent with the documented role of this pathway in the dissolution of tight junctions. Taken together, our data demonstrate that TGFßR3-dependent endocardial cell EMT stimulated by either TGFß2 or BMP-2 requires Smad4 and the activation of the Par6/Smurf1 pathway.

Endocardial cells are a distinct endothelial lineage derived from Flk1+ multipotent cardiovascular progenitors.

Identification of multipotent cardiac progenitors has provided important insights into the mechanisms of myocardial lineage specification, yet has done little to clarify the origin of the endocardium. Despite its essential role in heart development, characterization of the endocardial lineage has been limited by the lack of specific markers of this early vascular subpopulation. To distinguish endocardium from other vasculature, we generated an NFATc1-nuc-LacZ BAC transgenic mouse line capable of labeling this specific endothelial subpopulation at the earliest stages of cardiac development. To further characterize endocardiogenesis, embryonic stem cells (ESCs) derived from NFATc1-nuc-LacZ blastocysts were utilized to demonstrate that endocardial differentiation in vitro recapitulates the close temporal-spatial relationship observed between myocardium and endocardium seen in vivo. Endocardium is specified as a cardiac cell lineage, independent from other vascular populations, responding to BMP and Wnt signals that enhance cardiomyocyte differentiation. Furthermore, a population of Flk1+ cardiovascular progenitors, distinct from hemangioblast precursors, represents a mesodermal precursor of the endocardial endothelium, as well as other cardiovascular lineages. Taken together, these studies emphasize that the endocardium is a unique cardiac lineage and provides further evidence that endocardium and myocardium are derived from a common precursor.

Fate mapping using Cited1-CreERT2 mice demonstrates that the cap mesenchyme contains self-renewing progenitor cells and gives rise exclusively to nephronic epithelia.

Classic tissue recombination and in vitro lineage tracing studies suggest that condensed metanephric mesenchyme (MM) gives rise to nephronic epithelium of the adult kidney. However, these studies do not distinguish between cap mesenchyme and pre-tubular aggregates comprising the condensed MM, nor do they establish whether these cells have self-renewing capacity. To address these questions, we generated Cited1-CreER(T2) BAC transgenic mice, which express tamoxifen-regulated Cre recombinase exclusively in the cap mesenchyme. Fate mapping was performed by crossing these mice with the Rosa26R(LacZ) reporter line and evaluating the location and cellular characteristics of LacZ positive cells at different time points following tamoxifen injection. These studies confirmed expected results from previous in vitro analysis of MM cell fate, and provide in vivo evidence that the cap mesenchyme does not contribute to collecting duct epithelium in the adult. Furthermore, by exploiting the temporally regulated Cre recombinase, these studies show that nephronic epithelium arising at different stages of nephrogenesis has distinct spatial distribution in the adult kidney, and demonstrate for the first time that the cap mesenchyme includes a population of self-renewing epithelial progenitor cells.