Synergistic association of fluid overload and acute kidney injury on outcomes in pediatric cardiac ECMO: a retrospective analysis of the KIDMO database.

BACKGROUND: Acute kidney injury (AKI) and fluid overload (FO) are associated with poor outcomes in children receiving extracorporeal membrane oxygenation (ECMO). Our objective is to evaluate the impact of AKI and FO on pediatric patients receiving ECMO for cardiac pathology. METHODS: We performed a secondary analysis of the six-center Kidney Interventions During Extracorporeal Membrane Oxygenation (KIDMO) database, including only children who underwent ECMO for cardiac pathology. AKI was defined using Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria. FO was defined as < 10% (FO-) vs. ≥ 10% (FO +) and was evaluated at ECMO initiation, peak during ECMO, and ECMO discontinuation. Primary outcomes were mortality and length of stay (LOS). RESULTS: Data from 191 patients were included. Non-survivors (56%) were more likely to be FO + than survivors at peak ECMO fluid status and ECMO discontinuation. There was a significant interaction between AKI and FO. In the presence of AKI, the adjusted odds of mortality for FO + was 4.79 times greater than FO- (95% CI: 1.52-15.12, p = 0.01). In the presence of FO + , the adjusted odds of mortality for AKI + was 2.7 times higher than AKI- [95%CI: 1.10-6.60; p = 0.03]. Peak FO + was associated with a 55% adjusted relative increase in LOS [95%CI: 1.07-2.26, p = 0.02]. CONCLUSIONS: The association of peak FO + with mortality is present only in the presence of AKI + . Similarly, AKI + is associated with mortality only in the presence of peak FO + . FO + was associated with LOS. Studies targeting fluid management have the potential to improve LOS and mortality outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.

Trends in Neonatal Extracorporeal Membrane Oxygenation During a Venovenous Cannula Shortage.

OBJECTIVES: To report temporal trends in venovenous extracorporeal membrane oxygenation (ECMO) use for neonatal respiratory failure in U.S. centers before and after functional venovenous cannula shortage due to withdrawal of one dual lumen venovenous cannula from the market in 2018. DESIGN: Retrospective cohort study. SETTING: ECMO registry of the Extracorporeal Life Support Organization. PATIENTS: Infants who received neonatal (cannulated prior to 29 d of age) respiratory ECMO at a U.S. center and had a record available in the ECMO registry from January 1, 2010 to July 20, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was receipt of venovenous ECMO (vs venoarterial or other), and secondary outcomes were survival to hospital discharge and adverse neurologic outcomes. Using an interrupted time series design, we fit multivariable mixed effects logistic regression models with receipt of venovenous ECMO as the dependent variable, treatment year modeled as a piecewise linear variable using three linear splines (pre shortage: 2010-2014, 2014-2018; shortage: 2018-2021), and adjusted for center clustering and multiple covariates. We evaluated trends in venovenous ECMO use by primary diagnosis including congenital diaphragmatic hernia, meconium aspiration, pulmonary hypertension, and other. Annual neonatal venovenous ECMO rates decreased after 2018: from 2010 to 2014, adjusted odds ratio (aOR) for yearly trend 0.98 (95% CI 0.92-1.04), from 2014 to 2018, aOR for yearly trend 0.90 (95% CI 0.80-1.01), and after 2018, aOR for yearly trend 0.46 (95% CI 0.37-0.57). We identified decreased venovenous ECMO use after 2018 in all diagnoses evaluated, and we failed to identify differences in temporal trends between diagnoses. Survival and adverse neurologic outcomes were unchanged across the study periods. CONCLUSIONS: Venovenous ECMO for neonatal respiratory failure in U.S. centers decreased after 2018 even after accounting for temporal trends, coincident with withdrawal of one of two venovenous cannulas from the market.

Extracorporeal Life Support for Respiratory Failure in Patients With Electronic Cigarette or Vaping Product Use-Associated Lung Injury.

OBJECTIVES: Electronic cigarette or vaping product use-associated lung injury is a clinical entity that can lead to respiratory failure and death. Despite the severity of electronic cigarette or vaping product use-associated lung injury, the role of extracorporeal life support in its management remains unclear. Our objective was to describe the clinical characteristics and outcomes of patients with electronic cigarette or vaping product use-associated lung injury who received extracorporeal life support. DESIGN: We performed a retrospective review of records of electronic cigarette or vaping product use-associated lung injury patients who received extracorporeal life support. Standardized data were collected via direct contact with extracorporeal life support centers. Data regarding presentation, ventilatory management, extracorporeal life support details, and outcome were analyzed. SETTING: This was a multi-institutional, international case series with patients from 10 different institutions in three different countries. PATIENTS: Patients who met criteria for confirmed electronic cigarette or vaping product use-associated lung injury (based on previously reported diagnostic criteria) and were placed on extracorporeal life support were included. Patients were identified via literature review and by direct contact with extracorporeal life support centers. MEASUREMENTS AND MAIN RESULTS: Data were collected for 14 patients ranging from 16 to 45 years old. All had confirmed vape use within 3 months of presentation. Nicotine was the most commonly used vaping product. All patients had respiratory symptoms and radiographic evidence of bilateral pulmonary opacities. IV antibiotics and corticosteroids were universally initiated. Patients were intubated for 1.9 days (range, 0-6) prior to extracorporeal life support initiation. Poor oxygenation and ventilation were the most common indications for extracorporeal life support. Five patients showed evidence of ventricular dysfunction on echocardiography. Thirteen patients (93%) were placed on venovenous extracorporeal life support, and one patient required multiple rounds of extracorporeal life support. Total extracorporeal life support duration ranged from 2 to 37 days. Thirteen patients survived to hospital discharge; one patient died of septic shock. CONCLUSIONS: Electronic cigarette or vaping product use-associated lung injury can cause refractory respiratory failure and hypoxemia. These data suggest that venovenous extracorporeal life support can be an effective treatment option for profound, refractory respiratory failure secondary to electronic cigarette or vaping product use-associated lung injury.

Acute Kidney Injury, Fluid Overload, and Renal Replacement Therapy Differ by Underlying Diagnosis in Neonatal Extracorporeal Support and Impact Mortality Disparately.

INTRODUCTION: We aimed to characterize acute kidney injury (AKI), fluid overload (FO), and renal replacement therapy (RRT) utilization by diagnostic categories and examine associations between these complications and mortality by category. METHODS: To test our hypotheses, we conducted a retrospective multicenter, cohort study including 446 neonates (categories: 209 with cardiac disease, 114 with congenital diaphragmatic hernia [CDH], 123 with respiratory disease) requiring extracorporeal membrane oxygenation (ECMO) between January 1, 2007, and December 31, 2011. RESULTS: AKI, FO, and RRT each varied by diagnostic category. AKI and RRT receipt were most common in those neonates with cardiac disease. Subjects with CDH had highest peak %FO (51% vs. 28% cardiac vs. 32% respiratory; p < 0.01). Hospital survival was 55% and varied by diagnostic category (45% cardiac vs. 48% CDH vs. 79% respiratory; p < 0.001). A significant interaction suggested risk of mortality differed by diagnostic category in the presence or absence of AKI. In its absence, diagnosis of CDH (vs. respiratory disease) (OR 3.04, 95% CL 1.14-8.11) independently predicted mortality. In all categories, peak %FO (OR 1.20, 95% CL 1.11-1.30) and RRT receipt (OR 2.12, 95% CL 1.20-3.73) were independently associated with mortality. DISCUSSION/CONCLUSIONS: Physiologically distinct ECMO diagnoses warrant individualized treatment strategies given variable incidence and effects of AKI, FO, and RRT by category on mortality.

Acute kidney injury risk-based screening in pediatric inpatients: a pragmatic randomized trial.

BACKGROUND: Pediatric acute kidney injury (AKI) is common and associated with increased morbidity, mortality, and length of stay. We performed a pragmatic randomized trial testing the hypothesis that AKI risk alerts increase AKI screening. METHODS: All intensive care and ward admissions of children aged 28 days through 21 years without chronic kidney disease from 12/6/2016 to 11/1/2017 were included. The intervention alert displayed if calculated AKI risk was > 50% and no serum creatinine (SCr) was ordered within 24 h. The primary outcome was SCr testing within 48 h of AKI risk > 50%. RESULTS: Among intensive care admissions, 973/1909 (51%) were randomized to the intervention. Among those at risk, more SCr tests were ordered for the intervention group than for controls (418/606, 69% vs. 361/597, 60%, p = 0.002). AKI incidence and severity were the same in intervention and control groups. Among ward admissions, 5492/10997 (50%) were randomized to the intervention, and there were no differences between groups in SCr testing, AKI incidence, or severity of AKI. CONCLUSIONS: Alerts based on real-time prediction of AKI risk increased screening rates in intensive care but not pediatric ward settings. Pragmatic clinical trials provide the opportunity to assess clinical decision support and potentially eliminate ineffective alerts.

Fluid overload and fluid removal in pediatric patients on extracorporeal membrane oxygenation requiring continuous renal replacement therapy: a multicenter retrospective cohort study.

OBJECTIVE: The aim of this study was to characterize continuous renal replacement therapy (CRRT) utilization on extracorporeal membrane oxygenation (ECMO) and to determine the association of both fluid overload (FO) at CRRT initiation and fluid removal during CRRT with mortality in a large multicenter cohort. METHODS: Retrospective chart review of all children < 18 years of age concurrently treated with ECMO and CRRT from January 1, 2007, to December 31, 2011, at six tertiary care children's hospital. Children treated with hemodialysis or peritoneal dialysis were excluded from the FO analysis. MEASUREMENTS AND MAIN RESULTS: A total of 756 of the 1009 children supported with ECMO during the study period had complete FO data. Of these, 357 (47.2%) received either CRRT or were treated with an in-line filter and thus entered into the final analysis. Survival to ECMO decannulation was 66.4% and survival to hospital discharge was 44.3%. CRRT initiation occurred at median of 1 day (IQR 0, 2) after ECMO initiation. Median FO at CRRT initiation was 20.1% (IQR 5, 40) and was significantly lower in ECMO survivors vs. non-survivors (15.3% vs. 30.5% p = 0.005) and in hospital survivors vs. non-survivors (13.5% vs. 25.9%, p = 0.004). Median FO at CRRT discontinuation was significantly lower in ECMO survivors (23% vs. 37.6% p = 0.002) and hospital survivors vs. non-survivors (22.6% vs. 36.1%, p = 0.002). In ECMO survivors, after adjusting for pH at CRRT initiation, non-renal complications, ECMO mode, support type, center, patient age and AKI, FO at CRRT initiation (p = 0.01), and FO at CRRT discontinuation (p = 0.0002) were independently associated with duration of ECMO. In a similar multivariable analysis, FO at CRRT initiation (adjusted adds ratio [aOR] 1.09, 95% CI 1.00-1.18, p = 0.045) and at CRRT discontinuation (aOR 1.11, 95% CI 1.03-1.19, p = 0.01) were independently associated with hospital mortality. CONCLUSIONS: In a multicenter pediatric ECMO cohort, this study demonstrates that severe FO was very common at CRRT initiation. We found an independent association between the degree of FO at CRRT initiation with adverse outcomes including mortality and increased duration of ECMO support. The results suggest that intervening prior to the development of significant FO may be a clinical therapeutic target and warrants further evaluation.

Extracorporeal Membrane Oxygenation Support for Pediatric Burn Patients: Is It Worth the Risk?

OBJECTIVES: Examine the outcomes of pediatric burn patients requiring extracorporeal membrane oxygenation to determine whether extracorporeal membrane oxygenation should be considered in this special population. DESIGN: Retrospective cohort study. SETTING: All extracorporeal membrane oxygenation centers reporting to the Extracorporeal Life Support Organization. SUBJECTS: Pediatric patients (birth to younger than 18 yr) who were supported with extracorporeal membrane oxygenation with a burn diagnosis between 1990 and 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 113 patients were identified from the registry by inclusion criteria. Patients cannulated for respiratory failure had the highest survival (55.7%, n = 97) compared to those supported for cardiac failure (33.3%, n = 6) or extracorporeal cardiopulmonary resuscitation (30%, n = 10). Patients supported on venovenous extracorporeal membrane oxygenation for respiratory failure had the best overall survival at 62.2% (n = 37). Important for the burn population, rates of surgical site bleeding were similar to other surgical patients placed on extracorporeal membrane oxygenation at 22.1%. Cardiac arrest prior to cannulation was associated with increased hospital mortality (odds ratio, 3.41; 95% CI, 0.16-1.01; p = 0.048). Following cannulation, complications including the need for inotropes (odds ratio, 2.64; 95% CI, 1.24-5.65; p = 0.011), presence of gastrointestinal hemorrhage (p = 0.049), and hyperglycemia (glucose > 240 mg/dL) (odds ratio, 3.42; 95% CI, 1.13-10.38; p = 0.024) were associated with increased mortality. Of patients with documented burn percentage of total body surface area (n = 19), survival was 70% when less than 60% total body surface area was involved. CONCLUSIONS: Extracorporeal membrane oxygenation could be considered as an additional level of support for the pediatric burn population, especially in the setting of respiratory failure. Additional studies are necessary to determine the optimal timing of cannulation and other patient characteristics that may impact outcomes.

Arginine methylation regulates c-Myc-dependent transcription by altering promoter recruitment of the acetyltransferase p300.

Protein arginine methyltransferase 1 (PRMT1) is an essential enzyme controlling about 85% of the total cellular arginine methylation in proteins. We have shown previously that PRMT1 is an important regulator of innate immune responses and that it is required for M2 macrophage differentiation. c-Myc is a transcription factor that is critical in regulating cell proliferation and also regulates the M2 transcriptional program in macrophages. Here, we sought to determine whether c-Myc in myeloid cells is regulated by PRMT1-dependent arginine methylation. We found that PRMT1 activity was necessary for c-Myc binding to the acetyltransferase p300. PRMT1 inhibition decreased p300 recruitment to c-Myc target promoters and increased histone deacetylase 1 (HDAC1) recruitment, thereby decreasing transcription at these sites. Moreover, PRMT1 inhibition blocked c-Myc-mediated induction of several of its target genes, including peroxisome proliferator-activated receptor γ (PPARG) and mannose receptor C-type 1 (MRC1), suggesting that PRMT1 is necessary for c-Myc function in M2 macrophage differentiation. Of note, in primary human blood monocytes, p300-c-Myc binding was strongly correlated with PRMT1 expression, and in liver sections, PRMT1, c-Myc, and M2 macrophage levels were strongly correlated with each other. Both PRMT1 levels and M2 macrophage numbers were significantly lower in livers from individuals with a history of spontaneous bacterial peritonitis, known to have defective cellular immunity. In conclusion, our findings demonstrate that PRMT1 is an important regulator of c-Myc function in myeloid cells. PRMT1 loss in individuals with cirrhosis may contribute to their immune defects.

Protein arginine methyltransferase 1 modulates innate immune responses through regulation of peroxisome proliferator-activated receptor γ-dependent macrophage differentiation.

Arginine methylation is a common posttranslational modification that has been shown to regulate both gene expression and extranuclear signaling events. We recently reported defects in protein arginine methyltransferase 1 (PRMT1) activity and arginine methylation in the livers of cirrhosis patients with a history of recurrent infections. To examine the role of PRMT1 in innate immune responses in vivo, we created a cell type-specific knock-out mouse model. We showed that myeloid-specific PRMT1 knock-out mice demonstrate higher proinflammatory cytokine production and a lower survival rate after cecal ligation and puncture. We found that this defect is because of defective peroxisome proliferator-activated receptor γ (PPARγ)-dependent M2 macrophage differentiation. PPARγ is one of the key transcription factors regulating macrophage polarization toward a more anti-inflammatory and pro-resolving phenotype. We found that PRMT1 knock-out macrophages failed to up-regulate PPARγ expression in response to IL4 treatment resulting in 4-fold lower PPARγ expression in knock-out cells than in wild-type cells. Detailed study of the mechanism revealed that PRMT1 regulates PPARγ gene expression through histone H4R3me2a methylation at the PPARγ promoter. Supplementing with PPARγ agonists rosiglitazone and GW1929 was sufficient to restore M2 differentiation in vivo and in vitro and abrogated the difference in survival between wild-type and PRMT1 knock-out mice. Taken together these data suggest that PRMT1-dependent regulation of macrophage PPARγ expression contributes to the infection susceptibility in PRMT1 knock-out mice.

Electronic health record-based predictive models for acute kidney injury screening in pediatric inpatients.

BackgroundAcute kidney injury (AKI) is common in pediatric inpatients and is associated with increased morbidity, mortality, and length of stay. Its early identification can reduce severity.MethodsTo create and validate an electronic health record (EHR)-based AKI screening tool, we generated temporally distinct development and validation cohorts using retrospective data from our tertiary care children's hospital, including children aged 28 days through 21 years with sufficient serum creatinine measurements to determine AKI status. AKI was defined as 1.5-fold or 0.3 mg/dl increase in serum creatinine. Age, medication exposures, platelet count, red blood cell distribution width, serum phosphorus, serum transaminases, hypotension (ICU only), and pH (ICU only) were included in AKI risk prediction models.ResultsFor ICU patients, 791/1,332 (59%) of the development cohort and 470/866 (54%) of the validation cohort had AKI. In external validation, the ICU prediction model had a c-statistic=0.74 (95% confidence interval 0.71-0.77). For non-ICU patients, 722/2,337 (31%) of the development cohort and 469/1,474 (32%) of the validation cohort had AKI, and the prediction model had a c-statistic=0.69 (95% confidence interval 0.66-0.72).ConclusionsAKI screening can be performed using EHR data. The AKI screening tool can be incorporated into EHR systems to identify high-risk patients without serum creatinine data, enabling targeted laboratory testing, early AKI identification, and modification of care.

Cell Death and Prognosis of Mortality in Alcoholic Hepatitis Patients Using Plasma Keratin-18.

Alcoholic liver disease encompasses the progressive stages of liver dysfunction that culminates in alcoholic cirrhosis (AC) and in severe cases alcoholic hepatitis (AH). Currently, prognostic scores have limited specificity and sensitivity. Plasma keratin-18 (K18) levels are elevated during liver disease and may be biomarkers of outcome. The objective of this study was to determine if total K18 (M65) or caspase-cleaved K18 (M30) levels were different between AC and AH patients. M65 and M30 levels were measured in the plasma of consented healthy controls and patients with AC and AH. Cell death was assessed by TUNEL staining and caspase activity. M65 and M30 values were significantly higher in AC patients compared to healthy controls and further increased in AH patients. The M65 values and the M30/M65 ratios of nonsurviving AH patients were significantly elevated above their surviving counterparts and healthy controls. Statistical analysis indicated that M30/M65 ratios outperformed current indices for accurately distinguishing the prognosis of AH patients. These scores occurred with minimal increase in plasma cell death markers such as ALT and AST. Serum caspase activity, TUNEL staining, and M30 immunohistochemistry in biopsies indicated that serum and tissue values may not correlate well with overall cell death. In conclusion, both M65 and M30 differentiate AH from AC patients, and M65 values and the M30/M65 ratio are capable of predicting early stage mortality; however, they may not accurately reflect pure hepatocyte cell death in these populations, as they do not strongly correlate with traditional cell death markers.

The Impact of Fluid Overload on Outcomes in Children Treated With Extracorporeal Membrane Oxygenation: A Multicenter Retrospective Cohort Study.

OBJECTIVE: To characterize the epidemiology of fluid overload and its association with mortality and duration of extracorporeal membrane oxygenation in children treated with extracorporeal membrane oxygenation. DESIGN: Retrospective cohort study. SETTING: Six tertiary children's hospital ICUs. PATIENTS: Seven hundred fifty-six children younger than 18 years old treated with extracorporeal membrane oxygenation for greater than or equal to 24 hours from January 1, 2007, to December 31, 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Overall survival to extracorporeal membrane oxygenation decannulation and hospital discharge was 74.9% (n = 566) and 57.7% (n = 436), respectively. Median fluid overload at extracorporeal membrane oxygenation initiation was 8.8% (interquartile range, 0.3-19.2), and it differed between hospital survivors and non survival, though not between extracorporeal membrane oxygenation survivors and non survivors. Median peak fluid overload on extracorporeal membrane oxygenation was 30.9% (interquartile range, 15.4-54.8). During extracorporeal membrane oxygenation, 84.8% had a peak fluid overload greater than or equal to 10%; 67.2% of patients had a peak fluid overload of greater than or equal to 20% and 29% of patients had a peak fluid overload of greater than or equal to 50%. The median peak fluid overload was lower in patients who survived on extracorporeal membrane oxygenation (27.2% vs 44.4%; p < 0.0001) and survived to hospital discharge (24.8% vs 43.3%; p < 0.0001). After adjusting for acute kidney injury, pH at extracorporeal membrane oxygenation initiation, nonrenal complications, extracorporeal membrane oxygenation mode, support type, center and patient age, the degree of fluid overload at extracorporeal membrane oxygenation initiation (p = 0.05), and the peak fluid overload on extracorporeal membrane oxygenation (p < 0.0001) predicted duration of extracorporeal membrane oxygenation in survivors. Multivariable analysis showed that peak fluid overload on extracorporeal membrane oxygenation (adjusted odds ratio, 1.09; 95% CI, 1.04-1.15) predicted mortality on extracorporeal membrane oxygenation; fluid overload at extracorporeal membrane oxygenation initiation (adjusted odds ratio, 1.13; 95% CI, 1.05-1.22) and peak fluid overload (adjusted odds ratio, 1.18; 95% CI, 1.12-1.24) both predicted hospital morality. CONCLUSIONS: Fluid overload occurs commonly and is independently associated with adverse outcomes including increased mortality and increased duration of extracorporeal membrane oxygenation in a broad pediatric extracorporeal membrane oxygenation population. These results suggest that fluid overload is a potential target for intervention to improve outcomes in children on extracorporeal membrane oxygenation.

Acute Kidney Injury Incidence in Noncritically Ill Hospitalized Children, Adolescents, and Young Adults: A Retrospective Observational Study.

BACKGROUND: Acute kidney injury (AKI) has been characterized in high-risk pediatric hospital inpatients, in whom AKI is frequent and associated with increased mortality, morbidity, and length of stay. The incidence of AKI among patients not requiring intensive care is unknown. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 13,914 noncritical admissions during 2011 and 2012 at our tertiary referral pediatric hospital were evaluated. Patients younger than 28 days or older than 21 years of age or with chronic kidney disease (CKD) were excluded. Admissions with 2 or more serum creatinine measurements were evaluated. FACTORS: Demographic features, laboratory measurements, medication exposures, and length of stay. OUTCOME: AKI defined as increased serum creatinine level in accordance with KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Based on time of admission, time interval requirements were met in 97% of cases, but KDIGO time window criteria were not strictly enforced to allow implementation using clinically obtained data. RESULTS: 2 or more creatinine measurements (one baseline before or during admission and a second during admission) in 2,374 of 13,914 (17%) patients allowed for AKI evaluation. A serum creatinine difference ≥0.3mg/dL or ≥1.5 times baseline was seen in 722 of 2,374 (30%) patients. A minimum of 5% of all noncritical inpatients without CKD in pediatric wards have an episode of AKI during routine hospital admission. LIMITATIONS: Urine output, glomerular filtration rate, and time interval criteria for AKI were not applied secondary to study design and available data. The evaluated cohort was restricted to patients with 2 or more clinically obtained serum creatinine measurements, and baseline creatinine level may have been measured after the AKI episode. CONCLUSIONS: AKI occurs in at least 5% of all noncritically ill hospitalized children, adolescents, and young adults without known CKD. Physicians should increase their awareness of AKI and improve surveillance strategies with serum creatinine measurements in this population so that exacerbating factors such as nephrotoxic medication exposures may be modified as indicated.

Global Trends in Extracorporeal Membranous Oxygenation Use and Survival of Patients With Influenza-Associated Illness.

OBJECTIVES: To determine the overall use of extracorporeal membranous oxygenation for influenza-associated illness and describe risk factors associated with mortality in these patients. DESIGN: Retrospective multicenter cohort analysis. SETTING: The international Extracorporeal Life Support Organization database was queried for patients with influenza-associated illness on extracorporeal membranous oxygenation from 1992 to 2014. PATIENTS: In total, 1,654 patients with influenza-associated illness on extracorporeal membranous oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic and clinical data collected included age, type of support, duration of support, type of microbial codetection, complications, and survival status at discharge. The primary outcome of interest was survival to hospital discharge. From 1992 to 2014, 1,688 (3%) of the 61,336 extracorporeal membranous oxygenation runs were due to influenza-associated illness reflecting 1,654 unique patients: 30 (2%) were neonates, 521 (31%) were pediatric patients, and 1,103 (67%) were adults. Extracorporeal membranous oxygenation use for influenza-associated illness increased from 1992 to 2014, with a marked increase in use after the 2009 H1N1 pandemic. Survival to hospital discharge of patients with influenza-associated illness on extracorporeal membranous oxygenation was 63% and was not affected by bacterial codetection. However, when patients with Staphylococcus aureus codetection were compared with those with another bacterial codetection, their survival to hospital discharge was significantly lower (52% vs 67%; p < 0.01). In a logistic regression model, the effect of S. aureus on in-hospital mortality varied by age group, with younger patients with S. aureus having increased in-hospital mortality. CONCLUSIONS: Extracorporeal membranous oxygenation use for individuals with influenza increased over time, particularly after the 2009 H1N1 pandemic, most notably among older adults. Survival to hospital discharge for patients with influenza on extracorporeal membranous oxygenation was slightly higher than survival to hospital discharge for respiratory illness due to any cause. Bacterial codetection was common among patients with influenza on extracorporeal membranous oxygenation and was associated with increased days on extracorporeal membranous oxygenation but not increased mortality. Only S. aureus codetection in children was associated with increased in-hospital mortality.

The Incidence of Acute Kidney Injury and Its Effect on Neonatal and Pediatric Extracorporeal Membrane Oxygenation Outcomes: A Multicenter Report From the Kidney Intervention During Extracorporeal Membrane Oxygenation Study Group.

OBJECTIVE: In a population of neonatal and pediatric patients on extracorporeal membrane oxygenation; to describe the prevalence and timing of acute kidney injury utilizing a consensus acute kidney injury definition and investigate the association of acute kidney injury with outcomes (length of extracorporeal membrane oxygenation and mortality). DESIGN: Multicenter retrospective observational cohort study. SETTING: Six pediatric extracorporeal membrane oxygenation centers. PATIENTS: Pediatric patients (age, < 18 yr) on extracorporeal membrane oxygenation at six centers during a period of January 1, 2007, to December 31, 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Complete data were analyzed for 832 patients on extracorporeal membrane oxygenation. Sixty percent of patients had acute kidney injury utilizing the serum creatinine Kidney Disease Improving Global Outcomes criteria (AKI) and 74% had acute kidney injury using the full Kidney Disease Improving Global Outcomes criteria including renal support therapy (AKI). Of those who developed acute kidney injury, it was present at extracorporeal membrane oxygenation initiation in a majority of cases (52% AKI and 65% AKI) and present by 48 hours of extracorporeal membrane oxygenation support in 86% (AKI) and 93% (AKI). When adjusted for patient age, center of support, mode of support, patient complications and preextracorporeal membrane oxygenation pH, the presence of acute kidney injury by either criteria was associated with a significantly longer duration of extracorporeal membrane oxygenation support (AKI, 152 vs 110 hr; AKI, 153 vs 99 hr) and increased adjusted odds of mortality at hospital discharge (AKI: odds ratio, 1.77; 1.22-2.55 and AKI: odds ratio, 2.50; 1.61-3.90). With the addition of renal support therapy to the model, acute kidney injury was associated with a longer duration of extracorporeal membrane oxygenation support (AKI, 149 vs 121 hr) and increased risk of mortality at hospital discharge (AKI: odds ratio, 1.52; 1.04-2.21). CONCLUSION: Acute kidney injury is present in 60-74% of neonatal-pediatric patients supported on extracorporeal membrane oxygenation and is present by 48 hours of extracorporeal membrane oxygenation support in 86-93% of cases. Acute kidney injury has a significant association with increased duration of extracorporeal membrane oxygenation support and increased adjusted odds of mortality at hospital discharge.

The use of an extracorporeal membrane oxygenation anticoagulation laboratory protocol is associated with decreased blood product use, decreased hemorrhagic complications, and increased circuit life.

OBJECTIVES: To determine if a comprehensive extracorporeal membrane oxygenation anticoagulation monitoring protocol results in fewer hemorrhagic complications, reduced blood product usage, and increased circuit life. DESIGN: In September 2011, we augmented our standard extracorporeal membrane oxygenation laboratory protocol to include anti-factor Xa assays, thromboelastography, and antithrombin measurements. We performed a retrospective chart review to determine outcomes for patients placed on extracorporeal membrane oxygenation prior to and after the initiation of our anticoagulation laboratory protocol. SETTING: Tertiary care, academic children's hospital. PATIENTS: All patients who were placed on extracorporeal membrane oxygenation at our institution from January 1, 2007, to September 30, 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 261 extracorporeal membrane oxygenation runs before the initiation of the protocol and 105 extracorporeal membrane oxygenation runs after the initiation of the protocol. There were no major changes to our extracorporeal membrane oxygenation circuit or changes to our transfusion threshold during the study period. The indication for extracorporeal membrane oxygenation, age, and severity of illness of the patients were similar before and after protocol initiation. Median blood product usage for packed RBCs, fresh frozen plasma, platelets, and cryoprecipitate decreased significantly after protocol initiation. The occurrence of cannula site bleeding decreased from 22% to 12% (p = 0.04), and surgical site bleeding decreased from 38% to 25% (p = 0.02). Median extracorporeal membrane oxygenation circuit life increased from 3.6 to 4.3 days (p = 0.02). A trend toward increased patient survival was noted, but it did not reach statistical significance. CONCLUSIONS: We demonstrate an association between an extracorporeal membrane oxygenation anticoagulation laboratory protocol using anti-factor Xa assays, thromboelastography, and antithrombin measurements and a decrease in blood product transfusion, a decrease in hemorrhagic complications, and an increase in circuit life. To our knowledge, this is the first study to demonstrate clinical benefit associated with the use of these laboratory values for patients on extracorporeal membrane oxygenation.

Timing of Kidney Replacement Therapy Initiation and Survival During Pediatric Extracorporeal Membrane Oxygenation: An Extracorporeal Life Support Organization Registry Study.

To characterize kidney replacement therapy (KRT) and pediatric extracorporeal membrane oxygenation (ECMO) outcomes and to identify the optimal timing of KRT initiation during ECMO associated with increased survival. Observational retrospective cohort study using the Extracorporeal Life Support Organization Registry database in children (0-18 yo) on ECMO from January 1, 2016, to December 31, 2020. Of the 14,318 ECMO runs analyzed, 26% of patients received KRT during ECMO. Patients requiring KRT before ECMO had increased mortality to ECMO decannulation (29% vs. 17%, OR 1.97, P < 0.001) and to hospital discharge (58% vs. 39%, OR 2.16, P < 0.001). Patients requiring KRT during ECMO had an increased mortality to ECMO decannulation (25% vs. 15%, OR 1.85, P < 0.001) and to hospital discharge (56% vs. 34%, OR 2.47, P < 0.001). Multivariable logistic regression demonstrated that the need for KRT during ECMO was an independent predictor for mortality to ECMO decannulation (OR 1.49, P < 0.001) and to hospital discharge (OR 2.02, P < 0.001). Patients initiated on KRT between 24 and 72 hours after cannulation were more likely to survive to ECMO decannulation and showed a trend towards survival to hospital discharge as compared to those initiated before 24 hours and after 72 hours.

Managing the kidney - The role of continuous renal replacement therapy in neonatal and pediatric ECMO.

Extracorporeal membrane oxygenation (ECMO) represents a lifesaving therapy utilized in in the most critically ill neonates and children with reversible cardiopulmonary failure. As a result of the severity of their critical illness these patients are among the highest risk populations for developing acute kidney injury (AKI) and disorders of fluid balance including the pathologic state of fluid overload (FO). In multiple studies AKI has been shown to occur commonly in 60-80% children treated with ECMO and is associated with adverse outcomes. In early studies evaluating ECMO in neonatal respiratory populations, the importance of fluid balance and the development of FO was recognized as an important contributor to adverse outcomes. Multiple single center studies and multicenter work have confirmed that FO occurs commonly across ECMO populations and is consistently associated with adverse outcomes. As a result of the high rates of AKI and the high rates of FO, continuous renal replacement therapy (CRRT) is increasingly utilized in neonatal and pediatric ECMO. In this state-of-the-art review, we cover the definitions, pathophysiology, incidence, and impact of AKI and FO in neonates and children supported with ECMO and summarize and appraise the evidence regarding the use of CRRT concurrently with ECMO. This review will cover the appropriate timing of this initiation, the options for providing CRRT with ECMO, overview of CRRT prescription, and the long-term implications of kidney support therapy in this population.

Impact of stem cell marker expression on recurrence of TACE-treated hepatocellular carcinoma post liver transplantation.

BACKGROUND: Liver transplantation is the most effective therapy for cirrhosis-associated hepatocellular carcinoma (HCC) but its utility is limited by post-transplant tumor recurrence. Use of the Milan, size-based criteria, has reduced recurrence rate to less than 10% but many patients remain ineligible. Reduction of tumor size with local therapies has been used to "downstage" patients to allow them to qualify for transplantation, but the optimal criteria to predict tumor recurrence in these latter patients has not been established. The existence of a progenitor cell population, sometimes called cancer stem cells (CSCs), has been proposed to be one mechanism accounting for the chemotherapy resistance and recurrence of hepatocellular carcinoma. The aim of this study was to determine if transcatheter arterial chemoemolization (TACE) treated tumors have increased CSC marker expression and whether these markers could be used to predict tumor recurrence. METHODS: Formalin fixed specimens were obtained from 39 HCC liver explants (23 with no treatment and 16 after TACE). Immunohistochemical staining was performed for EpCAM, CD44, CD90, and CD133. Staining for each marker was scored 0-3 by evaluating the number and intensity of positive tumor cells in 5 hpf of tumor in each specimen. RESULTS: TACE treated tumors displayed greater necrosis and fibrosis than non-TACE treated samples but there were no differences in morphology between the viable tumor cells of both groups. In TACE treated specimens, the staining of both EpCAM and CD133 was greater than in non-TACE specimens but CD44 and CD90 were the same. In the TACE group, the presence of high EpCAM staining was associated with tumor recurrence. Four of ten EpCAM high patients recurred while 0 of 6 EpCAM low patients recurred (P = 0.040). None of the other markers predicted recurrence. CONCLUSION: High pre-transplant EpCAM staining predicted HCC recurrence. This suggests that the abundance of tumor cells with a CSC phenotype may be a critical factor in the likelihood of tumor recurrence in patients receiving liver transplantation after TACE.