Geoffrey M. Fleming

Renal Replacement Therapy in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) is a lifesaving procedure used in neonates, children, and adults with severe, reversible, cardiopulmonary failure. On the basis of single-center studies, the incidence of AKI occurs in 70%-85% of ECMO patients. Those with AKI and those who require renal replacement therapy (RRT) are at high risk for mortality, independent of potentially confounding variables. Fluid overload is common in ECMO patients, and is one of the main indications for RRT. RRT to maintain fluid balance and metabolic control is common in some but not all centers. RRT on ECMO can be performed via an in-line hemofilter or by incorporating a standard continuous renal replacement machine into the ECMO circuit. Both of these methods require specific technical considerations to provide safe and effective RRT. This review summarizes available epidemiologic data and how they apply to our understanding of AKI pathophysiology during ECMO, identifies indications for RRT while on ECMO, reviews technical elements for RRT application in the setting of ECMO, and finally identifies specific research-focused questions that need to be addressed to improve outcomes in this at-risk population.

Acute renal failure during extracorporeal support in the pediatric cardiac patient.

End-organ dysfunction is associated with increased mortality in pediatric cardiac patients requiring extracorporeal support. We sought to characterize the odds of developing acute renal failure (ARF) as well as associated increases in mortality in this population. Records of all cardiac patients in our pediatric intensive care unit receiving extracorporeal membrane oxygenation (ECMO) over a 24 month period were reviewed for data with respect to their course. Acute renal failure was defined as fluid retention or electrolyte disturbance resulting in institution of continuous renal replacement therapy (CRRT), or a glomerular filtration rate (GFR) of <35 ml/min/1.73 m2. Analysis revealed 49 ECMO runs in 48 patients, with ARF present in 71.7%, and CRRT initiated in 58.7%. Odds for developing ARF increased by 60% per day of ECMO support (β 1.60, 95% CI 1.08–2.37, p = 0.018). Acute renal failure during ECMO, after adjusting for patient age, remained associated with a decrease in odds of survival to discharge (OR 4.7, 95% CI 1.10–20.4, p = 0.037). We conclude that ARF is more common among pediatric cardiac patients requiring extracorporeal support than previously recognized. Increasing duration of ECMO support is associated with development of ARF. Acute renal failure while on ECMO is associated with a significant decrease in the odds of survival in the pediatric cardiac patient.

A multicenter international survey of renal supportive therapy during ECMO: The Kidney Intervention during Extracorporeal Membrane Oxygenation (KIDMO) group

Acute kidney injury and fluid overload (FO) are associated with increased mortality in critically ill patients, including the subset supported with extracorporeal membrane oxygenation (ECMO). The indication for and method of application of renal support therapy (RST) during ECMO is largely unknown beyond single-center experiences. The current study uses a survey design to document practice variation regarding RST, including indication, method of interface with the ECMO circuit, and prescribing practices. Sixty-five international ECMO centers (31%) responded to an online electronic survey regarding RST during ECMO. Nearly a quarter of centers (23%) reported using no RST during ECMO. Among those using the therapy, the predominant mode of therapy applied was convection and included slow continuous ultrafiltration and continuous venovenous hemofiltration. The predominant indication for RST was the treatment (43%) or prevention (16%) of FO. Nephrology rather than critical care medicine is reported as the prescribing service in a majority of centers with a significant difference between US centers and non-US centers. The results of this study identify a wide variation in practice regarding RST during ECMO that will offer multiple important avenues for further research by this group and others regarding the interface of RST and ECMO.

Hepatopulmonary syndrome: Use of extracorporeal life support for life‐threatening hypoxia following liver transplantation

Hepatopulmonary syndrome is an uncommon complication of nonacute liver failure, and in rare cases, hypoxia may be the presenting sign of liver dysfunction. The condition, once thought to be a contraindication, is improved in most cases by transplantation. There is a significant risk of postoperative, hypoxia‐related morbidity and mortality in patients with hepatopulmonary syndrome. We present a case of life‐threatening hypoxia following liver transplantation for liver failure and associated hepatopulmonary syndrome, with successful management using extracorporeal membrane oxygenation. Liver Transpl 14:966–970, 2008.

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.

Epstein-Barr Virus–Induced Hemophagocytic Lymphohistiocytosis and X-Linked Lymphoproliferative Disease: A Mimicker of Sepsis in the Pediatric Intensive Care Unit

A rare complication of infection with the Epstein-Barr virus is the development of hemophagocytic lymphohistiocytosis. Although most cases of Epstein-Barr virus–induced hemophagocytic lymphohistiocytosis develop in immunocompetent individuals, the rare immunodeficiency X-linked lymphoproliferative disease is often unmasked by Epstein-Barr virus infection and is clinically indistinguishable from Epstein-Barr virus–induced hemophagocytic lymphohistiocytosis. We describe the clinical course and management of a previously healthy 17-year-old boy who presented with hemodynamic collapse and severe systemic inflammatory response syndrome resulting from overwhelming hemophagocytosis in the setting of X-linked lymphoproliferative disease. A novel therapeutic approach using anti–tumor necrosis factor α therapy was instituted, aimed at attenuating the viral-induced hyperinflammatory state. Given the similarity to overwhelming sepsis, yet a substantially different therapeutic approach, this case illustrates the importance of early recognition and prompt treatment that are necessary to reduce the high morbidity and mortality associated with Epstein-Barr virus–induced hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease.

Mechanical component failures in 28,171 neonatal and pediatric extracorporeal membrane oxygenation courses from 1987 to 2006.

Objective: To provide a descriptive summary of mechanical component failure associated with extracorporeal membrane oxygenation (ECMO), and to examine patient and ECMO variables that may be associated with mechanical component failure and guide further study. We hypothesized that duration of ECMO, era of ECMO, indication for ECMO, age of patient, and center ECMO volume would be associated with mechanical component failure. Design: Retrospective cohort study. Patients and Methods: Extracorporeal Life Support Organization registry was queried for all neonatal and pediatric ECMO courses recorded. Each ECMO course was treated as an independent event, and was included if duration was ≥25 hrs with occurrence between 1987 and 2007. Courses with a duration >458 hrs or with an indication for ECMO during cardiopulmonary resuscitation were excluded from analysis. Mechanical component failure data were extracted from the Extracorporeal Life Support Organization registry for the oxygenator, raceway, other tubing, pigtail connectors, heat exchanger, and air in the circuit. Results: A total of 28,171 independent ECMO courses were included for analysis, of which 14.9% were associated with a mechanical component failure. Duration of ECMO, age group of patient, era of ECMO, and indication for ECMO were all associated with mechanical component failure. From our predictive model, we observed a continuous nonlinear relation suggesting increasing probability of mechanical component failure with increasing duration of ECMO support. Conclusions: Mechanical component failure over the course of this study was infrequent during neonatal and pediatric ECMO, and declined across eras as experience with the therapy grew. Increasing duration of ECMO was associated with an increasing probability of mechanical component failure. Indication for ECMO and patient age were also statistically associated with mechanical component failure probability, but ECMO center volume was not.

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 m2/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 m2/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.

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 (AKISCr) and 74% had acute kidney injury using the full Kidney Disease Improving Global Outcomes criteria including renal support therapy (AKISCr + RST). Of those who developed acute kidney injury, it was present at extracorporeal membrane oxygenation initiation in a majority of cases (52% AKISCr and 65% AKISCr + RST) and present by 48 hours of extracorporeal membrane oxygenation support in 86% (AKISCr) and 93% (AKISCr + RST). 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 (AKISCr, 152 vs 110 hr; AKISCr + RST, 153 vs 99 hr) and increased adjusted odds of mortality at hospital discharge (AKISCr: odds ratio, 1.77; 1.22–2.55 and AKISCr + RST: 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 (AKISCr, 149 vs 121 hr) and increased risk of mortality at hospital discharge (AKISCr: 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.Objective In a population of neonatal and pediatric patients on extracorporeal membrane oxygenation (ECMO); to describe the incidence and timing of acute kidney injury (AKI) utilizing a consensus AKI definition and investigate the association of AKI with outcomes (length of ECMO and mortality).

A Case Series Describing the Use of Argatroban in Patients on Extracorporeal Circulation

Anticoagulation for extracorporeal life support (ECLS) is routinely achieved using heparin, which can be difficult in patients suspected of having heparin-induced thrombocytopenia. We describe a case series of five patients in which we used argatroban, a direct thrombin inhibitor, as an alternative to heparin for systemic anticoagulation during ECLS in patients suspected to have heparin-induced thrombocytopenia. Argatroban was used to achieve target systemic anticoagulation for activate clotting times between 210 and 230. Duration of argatroban use while on ECLS ranged from 6 to 184 hours. Argatroban dosage ranged from 0.2 to 3.5 &mgr;g/kg/min. Activated clotting times showed good agreement with aPTT. In conclusion, we illustrate that argatroban is a reasonable alternative to heparin anticoagulation for patients requiring ECLS.