Continuous renal replacement therapy and therapeutic plasma exchange in pediatric liver failure.

Patients with acute liver failure (ALF) and acute on chronic liver failure (ACLF) have significant morbidity and mortality. They require extracorporeal blood purification modalities like continuous renal replacement therapy (CRRT) and therapeutic plasma exchange (TPE) as a bridge to recovery or liver transplantation. Limited data are available on the outcomes of patients treated with these therapies. This is a retrospective single-center study of 23 patients from 2015 to 2022 with ALF/ACLF who underwent CRRT and TPE. We aimed to describe the clinical characteristics and outcomes of these patients. Median (IQR) age was 0.93 years (0.57, 9.88), range 16 days to 20 years. Ten (43%) had ALF and 13 (57%) ACLF. Most (n = 19, 82%) started CRRT for hyperammonemia and/or hepatic encephalopathy and all received TPE for refractory coagulopathy. CRRT was started at a median of 2 days from ICU admission, and TPE started on the same day in most. The liver transplant was done in 17 (74%), and 2 recovered native liver function. Four patients, all with ACLF, died prior to ICU discharge without a liver transplant. The median peak ammonia pre-CRRT was 131 µmol/L for the whole cohort. The mean (SD) drop in ammonia after 48 h of CRRT was 95.45 (43.72) µmol/L in those who survived and 69.50 (21.70) µmol/L in those who did not (p 0.26). Those who survived had 0 median co-morbidities compared to 2.5 in non-survivors (aOR (95% CI) for mortality risk of 2.5 (1.1-5.7), p 0.028). Conclusion: In this cohort of 23 pediatric patients with ALF or ACLF who received CRRT and TPE, 83% survived with a liver transplant or recovered with their native liver. Survival was worse in those who had ACLF and those with co-morbid conditions. What is Known: •  Pediatric acute liver failure is associated with high mortality. •  Patients may require extracorporeal liver assist therapies (like CRRT, TPE, MARS, SPAD) to bridge them over to a transplant or recovery of native liver function. What is New: • Standard volume plasma exhange has not been evaluated against high volume plasma exchange for ALF. • The role, dose, and duration of therapeutic plasma exchange in patients with acute on chronic liver failure is not well described.

Pediatric AKI in the real world: changing outcomes through education and advocacy-a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference.

BACKGROUND: Acute kidney injury (AKI) is independently associated with increased morbidity and mortality across the life course, yet care for AKI remains mostly supportive. Raising awareness of this life-threatening clinical syndrome through education and advocacy efforts is the key to improving patient outcomes. Here, we describe the unique roles education and advocacy play in the care of children with AKI, discuss the importance of customizing educational outreach efforts to individual groups and contexts, and highlight the opportunities created through innovations and partnerships to optimize lifelong health outcomes. METHODS: During the 26th Acute Disease Quality Initiative (ADQI) consensus conference, a multidisciplinary group of experts discussed the evidence and used a modified Delphi process to achieve consensus on recommendations on AKI research, education, practice, and advocacy in children. RESULTS: The consensus statements developed in response to three critical questions about the role of education and advocacy in pediatric AKI care are presented here along with a summary of available evidence and recommendations for both clinical care and research. CONCLUSIONS: These consensus statements emphasize that high-quality care for patients with AKI begins in the community with education and awareness campaigns to identify those at risk for AKI. Education is the key across all healthcare and non-healthcare settings to enhance early diagnosis and develop mitigation strategies, thereby improving outcomes for children with AKI. Strong advocacy efforts are essential for implementing these programs and building critical collaborations across all stakeholders and settings.

Acute Kidney Injury.

Acute kidney injury (AKI) has been shown to occur commonly in hospitalized children. AKI is associated with multiple complications, including elevated blood urea nitrogen level, electrolyte dyscrasias, acidosis, and fluid balance disorders. During the past 10 years, multiple multicenter studies have shown that AKI occurs commonly and is associated with adverse outcomes across a variety of populations in pediatrics. This state-of-the-art review provides a detailed overview and update on AKI, including definition, epidemiology, outcomes, differential diagnosis, diagnostics, and management of complications.

Consensus-Based Recommendations on Priority Activities to Address Acute Kidney Injury in Children: A Modified Delphi Consensus Statement.

Importance: Increasing evidence indicates that acute kidney injury (AKI) occurs frequently in children and young adults and is associated with poor short-term and long-term outcomes. Guidance is required to focus efforts related to expansion of pediatric AKI knowledge. Objective: To develop expert-driven pediatric specific recommendations on needed AKI research, education, practice, and advocacy. Evidence Review: At the 26th Acute Disease Quality Initiative meeting conducted in November 2021 by 47 multiprofessional international experts in general pediatrics, nephrology, and critical care, the panel focused on 6 areas: (1) epidemiology; (2) diagnostics; (3) fluid overload; (4) kidney support therapies; (5) biology, pharmacology, and nutrition; and (6) education and advocacy. An objective scientific review and distillation of literature through September 2021 was performed of (1) epidemiology, (2) risk assessment and diagnosis, (3) fluid assessment, (4) kidney support and extracorporeal therapies, (5) pathobiology, nutrition, and pharmacology, and (6) education and advocacy. Using an established modified Delphi process based on existing data, workgroups derived consensus statements with recommendations. Findings: The meeting developed 12 consensus statements and 29 research recommendations. Principal suggestions were to address gaps of knowledge by including data from varying socioeconomic groups, broadening definition of AKI phenotypes, adjudicating fluid balance by disease severity, integrating biopathology of child growth and development, and partnering with families and communities in AKI advocacy. Conclusions and Relevance: Existing evidence across observational study supports further efforts to increase knowledge related to AKI in childhood. Significant gaps of knowledge may be addressed by focused efforts.

Dialysis disequilibrium on CKRT: avoiding the steep slippery slope.

BACKGROUND: Current guidelines for initiation of kidney replacement do not include specific recommendations for prescription parameters and monitoring. CASE OUTLINE: A 16-year-old girl presented with kidney failure with creatinine of 19.8 mg/dL and BUN of 211 mg/dL. She initiated continuous kidney replacement therapy (CKRT) with clearance of 1,300 mL/min/1.73 m2 which was increased to 1,950 mL/min/1.73 m2 at 17 h of stable therapy. COMPLICATIONS: At 31 h of therapy, she developed generalized seizure activity. CT imaging was negative for acute intracranial process, and EEG demonstrated diffuse encephalopathy. CKRT was discontinued, and BUN was noted to be 47 mg/dL at that time (a 79% reduction from presenting BUN). KEY MANAGEMENT POINTS: • The potential for development of DDS is not isolated to intermittent hemodialysis and may occur later in presentation. • A decreased clearance rate should be considered in those with risk factors for development of dialysis disequilibrium syndrome (DDS). • Frequent monitoring of BUN/serum osmolality is important to allow for adjustment of the KRT prescription following initiation of therapy. • Additional research is needed to guide risk assessment for DDS and therapeutic timing and goals in the early stages of KRT initiation. • Inclusion of more specific guidelines surrounding DDS would assist in providing important support for nephrologists. LIST OF RELEVANT GUIDELINES: KDIGO clinical practice guideline for acute kidney injury [1] Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease [2] The Renal Association Clinical Practice Guideline Acute Kidney Injury (AKI) [3] The Japanese Clinical Practice Guideline for Acute Kidney Injury [4].

The association between fluid restriction and hyponatremia in newborns with gastroschisis.

INTRODUCTION: Newborns with gastroschisis require appropriate fluid resuscitation but are also at risk for hyponatremia that may lead to adverse outcomes. The etiology of hyponatremia in gastroschisis has not been defined. METHODS: Over a 24-month period, all newborns with gastroschisis in a free-standing pediatric hospital had sodium levels measured from serum, urine, gastric output, and the bowel bag around the eviscerated contents for the first 48 h of life. Total fluid intake and output were measured. Maintenance fluids were standardized at 120 mL/kg/day. Hyponatremia was defined as a serum sodium <132 mEq/L. A logistic regression model was created to determine independent predictors of hyponatremia. RESULTS: 28 infants were studied, and 14 patients underwent primary closure. While serum sodium was normal in all patients at birth, 9 (32%) infants developed hyponatremia at a median of 17.4 h of life. On univariate analysis, hyponatremic babies had a greater net positive fluid balance (74.9 vs 114.7 mL/kg, p = 0.001) primarily due to a decrease in total fluid output (p = 0.05). On multivariable regression, a 10 mL/kg increase in overall fluid balance was associated with an increased risk of developing hyponatremia (OR 1.84 [1.23, 3.45], p = 0.016). No differences in the sodium content of urine, gastric, or bowel bag fluid were observed, and sodium balance was equivalent between cohorts. DISCUSSION: Hyponatremia in babies with gastroschisis in the early postnatal period was associated with positive fluid balance and decreased fluid output. Prospective studies to determine the appropriate fluid resuscitation strategy in this population are warranted.

A prospective multi-center quality improvement initiative (NINJA) indicates a reduction in nephrotoxic acute kidney injury in hospitalized children.

Nephrotoxic medication (NTMx) exposure is a common cause of acute kidney injury (AKI) in hospitalized children. The Nephrotoxic Injury Negated by Just-in time Action (NINJA) program decreased NTMx associated AKI (NTMx-AKI) by 62% at one center. To further test the program, we incorporated NINJA across nine centers with the goal of reducing NTMx exposure and, consequently, AKI rates across these centers. NINJA screens all non-critically ill hospitalized patients for high NTMx exposure (over three medications on the same day or an intravenous aminoglycoside over three consecutive days), and then recommends obtaining a daily serum creatinine level in exposed patients for the duration of, and two days after, exposure ending. Additionally, substitution of equally efficacious but less nephrotoxic medications for exposed patients starting the day of exposure was recommended when possible. The main outcome was AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria (increase of 50% or 0.3 mg/dl over baseline). The primary outcome measure was AKI episodes per 1000 patient-days. Improvement was defined by statistical process control methodology and confirmed by Autoregressive Integrated Moving Average (ARIMA) modeling. Eight consecutive bi-weekly measure rates in the same direction from the established baseline qualified as special cause change for special process control. We observed a significant and sustained 23.8% decrease in NTMx-AKI rates by statistical process control analysis and by ARIMA modeling; similar to those of the pilot single center. Thus, we have successfully applied the NINJA program to multiple pediatric institutions yielding decreased AKI rates.

Healthcare recommendations for Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

Renal replacement therapy in the management of intoxications in children: recommendations from the Pediatric Continuous Renal Replacement Therapy (PCRRT) workgroup.

BACKGROUND: Intentional or unintentional ingestions among children and adolescents are common. There are a number of ingestions amenable to renal replacement therapy (RRT). METHODS: We systematically searched PubMed/Medline, Embase, and Cochrane databases for literature regarding drugs/intoxicants and treatment with RRT in pediatric populations. Two experts from the PCRRT (Pediatric Continuous Renal Replacement Therapy) workgroup assessed titles, abstracts, and full-text articles for extraction of data. The data from the literature search was shared with the PCRRT workgroup and two expert toxicologists, and expert panel recommendations were developed. RESULTS AND CONCLUSIONS: We have presented the recommendations concerning the use of RRTs for treatment of intoxications with toxic alcohols, lithium, vancomycin, theophylline, barbiturates, metformin, carbamazepine, methotrexate, phenytoin, acetaminophen, salicylates, valproic acid, and aminoglycosides.

C septicum Complicating Hemolytic Uremic Syndrome: Survival Without Surgical Intervention.

Clostridium septicum is an anaerobic bacterium that causes rapidly progressive myonecrosis, bacteremia, and central nervous system infection. It has been reported as a complication of Escherichia coli hemolytic uremic syndrome (HUS) in 8 children worldwide; 5 children died, and the 3 reported survivors had surgically treated disease. We present 3 cases of C septicum complicating HUS in children, including the first 2 reported cases of survival without surgical intervention. All patients presented with classic cases of HUS with initial clinical improvement followed by deterioration. Patient 1 had rising fever, tachycardia, and severe abdominal pain 24 hours after admission. She developed large multifocal intraparenchymal cerebral hemorrhages and died 12 hours later. Autopsy revealed C septicum intestinal necrosis, myonecrosis, and encephalitis. Patient 2 had new fever, increasing leukocytosis, and severe abdominal pain on hospital day 4. She was diagnosed with C septicum bacteremia and treated with metronidazole, meropenem, and clindamycin. Patient 3 had new fever and increasing leukocytosis on hospital day 3; blood cultures grew C septicum, and she was treated with penicillin. Patients 2 and 3 improved rapidly and did not require surgery. C septicum is a potential co-infection with E coli It thrives in the anaerobic environment of E coli-damaged intestinal mucosa and translocates to cause systemic infection. Fever, tachycardia, a rising white blood cell count, and abdominal pain out of proportion to examination are key findings for which physicians should be vigilant. Timely evaluation by anaerobic blood culture and early initiation of antibiotics are necessary to prevent fatalities.

Impact of Kidney Disease on Survival in Neonatal Extracorporeal Life Support.

OBJECTIVE: To investigate the prevalence and survival to discharge of neonates with kidney disease who received extracorporeal life support. DESIGN: We analyzed the Extracorporeal Life Support Organization international registry of neonates (< 30 d old) who received extracorporeal life support from 1989 to 2012. We used International Classification of Diseases and Related Health Problems, 9th Revision, Clinical Modification, codes to identify neonates with kidney disease at time of cannulation for extracorporeal life support. SETTING: Participating Extracorporeal Life Support Organization centers. PATIENTS: All neonates who received extracorporeal life support at an Extracorporeal Life Support Organization center from 1989 to 2012. INTERVENTIONS: We performed bivariate logistic regression to estimate associations between survival and covariates. We used unadjusted and adjusted logistic regression to compare survival to discharge between neonates with and without kidney disease. Odds ratios were estimated separately for three groups based on extracorporeal life support indication: pulmonary indication without congenital diaphragmatic hernia, pulmonary indication with congenital diaphragmatic hernia, and cardiac indication. Adjusted models included covariates identified as significant in bivariate models for each group. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was survival to discharge from hospitalization. Of the 28,755 neonates who received extracorporeal life support, 405 had kidney disease (extracorporeal life support indication: 210 pulmonary indication without congenital diaphragmatic hernia, 65 pulmonary indication with congenital diaphragmatic hernia, and 130 cardiac indication). Survival was lower in neonates with kidney disease than those without (49% vs 82% pulmonary indication without congenital diaphragmatic hernia, 25% vs 51% pulmonary indication with congenital diaphragmatic hernia, 21% vs 41% cardiac indication). Kidney disease was associated with reduced survival in adjusted models (95% CI for odds ratio 0.31-0.59 pulmonary indication without congenital diaphragmatic hernia, 0.27-0.89 pulmonary indication with congenital diaphragmatic hernia, 0.31-0.77 cardiac indication). CONCLUSIONS: Neonates with kidney disease who receive extracorporeal life support have poorer survival to discharge compared with other neonates who receive extracorporeal life support, suggesting that kidney disease should be considered when making extracorporeal life support initiation decisions.

Pediatric nephrologists' beliefs regarding randomized controlled trials.

BACKGROUND: Pediatrics and pediatric nephrology lag behind adult medicine in producing randomized controlled trials (RCTs). Physician attitudes have been shown to play a significant role in RCT enrollment. METHODS: We surveyed members of the American Society of Pediatric Nephrology regarding beliefs about RCTs and factors influencing decisions to recommend RCT enrollment. Regression analyses were used to identify the effects of variables on an aggregate score summarizing attitudes toward RCTs. RESULTS: One hundred thirty replies were received. Sixty-six percent had enrolled patients in RCTs. Respondents in practice for more than 15 years were more likely to have recruited a patient to an RCT than those in practice for less than 5 years. Respondents were more willing to recommend RCT enrollment if the study was multicenter, patients were sicker or had a poorer prognosis, or if the parent or participant received a financial incentive versus the provider. In multiple regression analysis, history of enrolling patients in an RCT was the only significant predictor of higher aggregate RCT-friendly attitude. CONCLUSIONS: Many pediatric nephrologists have never enrolled a patient in an RCT, particularly those in practice for less than 5 years. Respondents who have not enrolled patients in RCTs have a less RCT-friendly attitude. Provision of improved training and resources might increase participation of junior providers in RCTs.

Moving beyond supportive care--current status of specific therapies in pediatric acute kidney injury.

Acute kidney injury (AKI) remains a significant challenge, leading to increased morbidity, mortality, and medical costs. Therapy for AKI to this point has largely been supportive; specific interventions to treat established AKI have had minimal effect. Review of the pathogenesis of AKI reveals complex, interacting mechanisms, including changes in microcirculation, the immune system, and inflammation, and cell death from both necrosis and apoptosis. Past definitions of AKI have been imprecise; newer methods for AKI identification and classification, including novel biomarkers and improved criteria for defining AKI, may permit earlier intervention with greater potential for success. With improved understanding of pathophysiology and the opportunity for intervention before AKI is fully established, clinicians may be able to move beyond supportive care and improve outcomes.

Continuous renal replacement therapy with an automated monitor is superior to a free-flow system during extracorporeal life support.

OBJECTIVES: To determine whether integrated continuous renal replacement therapy provides more accurate fluid management than IV pump free-flow ultrafiltration in pediatric patients on extracorporeal life support. DESIGN: Retrospective study. SETTING: PICU and neonatal ICU in a tertiary academic center. PATIENTS: Infants and children less than 18 years old. INTERVENTIONS: Extracorporeal membrane oxygenation and continuous renal replacement therapy. MEASUREMENTS AND MAIN RESULTS: Clinical data collected on patients who received free-flow or integrated renal replacement therapy while on extracorporeal life support. Normalized ultrafiltration error was calculated as: (physician specified fluid loss per 24-hr period - actual fluid loss per 24-hr period) divided by patient body weight (kg). Mixed linear regression analyses were used to model longitudinal ultrafiltration error trajectories within each mode of ultrafiltration. Based on an analysis of 458 serial ultrafiltration fluid balance measurements, integrated ultrafiltration was significantly more accurate than free-flow ultrafiltration (normalized ultrafiltration error of 1.2 vs 13.1 mL; p < 0.001). After adjusting for patient factors and time, integrated ultrafiltration was associated with a significantly lower normalized ultrafiltration error (variable estimate, -24 ± 6; p < 0.001). The use of integrated ultrafiltration was associated with shorter duration of extracorporeal life support (384 vs 583 hr, p < 0.001) and renal replacement therapy (185 vs 477 hr, p < 0.001) than free-flow patients. Overall ICU and hospital length of stay and in-hospital mortality were similar between the groups. CONCLUSIONS: While free-flow ultrafiltration has the advantages of simplicity and low cost, integrated renal replacement therapy provides more accurate fluid management during extracorporeal life support. Better fluid status management with integrated renal replacement therapy may contribute to shorter duration of extracorporeal life support.

Continuous renal replacement therapy for children ≤10 kg: a report from the prospective pediatric continuous renal replacement therapy registry.

OBJECTIVE: To report circuit characteristics and survival analysis in children weighing ≤10 kg enrolled in the Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry. STUDY DESIGN: We conducted prospective cohort analysis of the ppCRRT Registry to: (1) evaluate survival differences in children ≤10 kg compared with other children; (2) determine demographic and clinical differences between surviving and non-surviving children ≤10 kg; and (3) describe continuous renal replacement therapy (CRRT) circuit characteristics differences in children ≤5 kg versus 5-10 kg. RESULTS: The ppCRRT enrolled 84 children ≤10 kg between January 2001 and August 2005 from 13 US tertiary centers. Children ≤10 kg had lower survival rates than children >10 kg (36/84 [43%] versus 166/260 [64%]; P < .001). In children ≤10 kg, survivors were more likely to have fewer days in intensive care unit prior to CRRT, lower Pediatric Risk of Mortality 2 scores at intensive care unit admission and lower mean airway pressure (P(aw)), higher urine output, and lower percent fluid overload (FO) at CRRT initiation. Adjusted regression analysis revealed that Pediatric Risk of Mortality 2 scores, FO, and decreased urine output were associated with mortality. Compared with circuits from children 5-10 kg at CRRT initiation, circuits from children ≤5 kg more commonly used blood priming for initiation, heparin anticoagulation, and higher blood flows/effluent flows for body weight. CONCLUSION: Mortality is more common in children who are ≤10 kg at the time of CRRT initiation. Like other CRRT populations, urine output and FO at CRRT initiation are independently associated with mortality. CRRT prescription differs in small children.

Nonrenal indications for continuous renal replacement therapy: A report from the Prospective Pediatric Continuous Renal Replacement Therapy Registry Group.

OBJECTIVE: Continuous renal replacement therapy is the most often implemented dialysis modality in the pediatric intensive care unit setting for patients with acute kidney injury. However, it also has a role in the management of patients with nonrenal indications such as clearance of drugs and intermediates of disordered cellular metabolism. MEASUREMENTS AND METHODS: Using data from the multicenter Prospective Pediatric Continuous Renal Replacement Therapy Registry, we report a cohort of pediatric patients receiving continuous renal replacement therapy for nonrenal indications. Nonrenal indications were obtained from the combination of "other" category for continuous renal replacement therapy initiation and patient diagnosis (both primary and secondary). This cohort was further divided into three subgroups: inborn errors of metabolism, drug toxicity, and tumor lysis syndrome. RESULTS: From 2000 to 2005, a total of 50 continuous renal replacement therapy events with nonrenal indications for therapy were included in the Prospective Pediatric Continuous Renal Replacement Therapy Registry. Indication-specific survival of the subgroups was 62% (inborn errors of metabolism), 82% (tumor lysis syndrome), and 95% (drug toxicity). The median small solute dose delivered among the subgroups ranged from 2125 to 8213 mL/1.73 m/hr, with 54%-59% receiving solely diffusion-based clearance as continuous venovenous hemodialysis. No association was established between survival and dose delivered, modality of continuous renal replacement therapy, or use of intermittent hemodialysis prior to continuous renal replacement therapy. CONCLUSIONS: Pediatric patients requiring continuous renal replacement therapy for nonrenal indications are a distinct cohort within the population receiving renal replacement therapy with little published experience of outcomes for this group. Survival within this cohort varies by indication for continuous renal replacement therapy and is not associated with continuous renal replacement therapy modality. Additionally, survival is not associated with small solute doses delivered within a cohort receiving >2000 mL/1.73 m/hr. Our data suggest metabolic control is established rapidly in pediatric patients and that acute detoxification may be provided with continuous renal replacement therapy for both the initial and maintenance phases of treatment using either convection or diffusion at appropriate doses.

Acute kidney injury: can we improve prognosis?

The incidence of pediatric acute kidney injury (AKI) is increasing. AKI has been found to be independently associated with increased mortality, and current management options are limited in that they are mainly supportive. The use of various definitions of AKI can still be found in the literature, making it difficult to discern the epidemiology behind pediatric AKI. The use of a more uniform definition is a necessary first step to clarify AKI epidemiology and direct our research efforts, and it will ultimately improve prognosis. There is evidence that neonates and infants may be at higher risk for AKI than adults. However, the least amount of research is found for this youngest age group, and more focused efforts on this population are necessary. This paper reviews existing data on and definitions for pediatric AKI, general preventive and treatment strategies, as well as ongoing research efforts on AKI. We are hopeful that the prognosis of AKI will improve with collaboration on a multicenter, multinational scale in the form of prospective, long-term studies on pediatric AKI.

Fluid overload and mortality in children receiving continuous renal replacement therapy: the prospective pediatric continuous renal replacement therapy registry.

BACKGROUND: Critically ill children with hemodynamic instability and acute kidney injury often develop fluid overload. Continuous renal replacement therapy (CRRT) has emerged as a favored modality in the management of such children. This study investigated the association between fluid overload and mortality in children receiving CRRT. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 297 children from 13 centers across the United States participating in the Prospective Pediatric CRRT Registry. PREDICTOR: Fluid overload from intensive care unit (ICU) admission to CRRT initiation, defined as a percentage equal to (fluid in [L] - fluid out [L])/(ICU admit weight [kg]) x 100%. OUTCOME & MEASUREMENTS: The primary outcome was survival to pediatric ICU discharge. Data were collected regarding demographics, CRRT parameters, underlying disease process, and severity of illness. RESULTS: 153 patients (51.5%) developed < 10% fluid overload, 51 patients (17.2%) developed 10%-20% fluid overload, and 93 patients (31.3%) developed > or = 20% fluid overload. Patients who developed > or = 20% fluid overload at CRRT initiation had significantly higher mortality (61/93; 65.6%) than those who had 10%-20% fluid overload (22/51; 43.1%) and those with < 10% fluid overload (45/153; 29.4%). The association between degree of fluid overload and mortality remained after adjusting for intergroup differences and severity of illness. The adjusted mortality OR was 1.03 (95% CI, 1.01-1.05), suggesting a 3% increase in mortality for each 1% increase in severity of fluid overload. When fluid overload was dichotomized to > or = 20% and < 20%, patients with > or = 20% fluid overload had an adjusted mortality OR of 8.5 (95% CI, 2.8-25.7). LIMITATIONS: This was an observational study; interventions were not standardized. The relationship between fluid overload and mortality remains an association without definitive evidence of causality. CONCLUSIONS: Critically ill children who develop greater fluid overload before initiation of CRRT experience higher mortality than those with less fluid overload. Further goal-directed research is required to accurately define optimal fluid overload thresholds for initiation of CRRT.