THE CLINICAL APPLICATION OF CRRTCURRENT STATUS

Overview of Pediatric Renal Replacement Therapy in Acute Kidney Injury

Stuart L. Goldstein
Department of Pediatrics, Baylor College of Medicine, Renal Dialysis Unit and Pheresis Service, Texas Childrens Hospital, and Prospective Pediatric Continuous Renal Replacement Therapy Registry, Houston, Texas

ABSTRACT The disease spectrum leading to pediatric renal replacement therapy (RRT) provision has broadened over the last decade. In the 1980s, intrinsic renal disease and burns comprised the most common pediatric acute kidney injury (AKI) etiologies. More recent data demonstrate that pediatric AKI most often results from complications of other systemic diseases resulting from the advancements in congenital heart surgery, neonatal care, and bone marrow and solid organ transplantation. In addition, RRT modality preferences to treat critically ill children have shifted from peritoneal dialysis to continuous renal replacement therapy (CRRT) as a result of improvements in CRRT technologies. Currently, multicenter prospective outcome studies for critically ill children with AKI are sorely lacking. The aims of this paper are to review the pediatric specic causes necessitating RRT provision with an emphasis on emerging practice patterns with respect to modality and the timing of treatment, and focus upon the application of the different RRT modalities and assessment of the outcome of children with AKI who receive RRT.

Provision of appropriate renal replacement therapy (RRT) for pediatric patients with acute kidney injury (AKI) requires special considerations not commonly encountered in the care of adult patients. Pediatric patients with AKI may range in weight from a 1.5 kg neonate to a 200 kg young adult. In addition, disease states that may require acute RRT in the absence of signicant renal dysfunction, such as inborn errors of metabolism or postoperative care of an infant with congenital cardiac defects, are more prevalent in the pediatric setting. Optimal care for the pediatric patient requiring RRT demands an understanding of the causes and patterns of pediatric AKI and multiorgan dysfunction syndrome (MODS) and recognition of the local expertise with respect to the personnel and equipment resources. The aim of this paper is to review the pediatric specic causes necessitating RRT provision with an emphasis on emerging practice patterns with respect to modality and the timing of treatment. Pediatric AKI Epidemiology Advancements and improvements in care for critically ill neonates, infants with congenital cardiac
Address for correspondence to: Stuart L. Goldstein, Texas Childrens Hospital, 6621 Fannin Street, Mail Code 3-2482, Houston, TX 77030, or e-mail: stuartg@bcm.edu. Seminars in DialysisVol 22, No 2 (MarchApril) 2009 pp. 180184 DOI: 10.1111/j.1525-139X.2008.00551.x 2009 Wiley Periodicals, Inc. 180

disease, and children with bone marrow and solid organ transplantation has led to a dramatic broadening of pediatric AKI epidemiology. While multicenter epidemiological pediatric AKI data do not exist, single center data from the 1980s report hemolytic uremic syndrome, other primary renal causes, sepsis, and burns as the most prevalent causes leading to pediatric AKI (13). More recent single center data detail the underlying causes of pediatric AKI in large cohorts of children and demonstrate an epidemiological shift where AKI is more often a comorbidity of another underlying disease or systemic process. Bunchman (4) reported data from 226 children with AKI treated with RRT with the most common causes being congenital heart disease, acute tubular necrosis (ATN), and sepsis. We reported data from 254 children with AKI, 80 of whom required RRT, and also found that ATN, congenital heart disease, and nephrotoxic medications were the most prevalent primary causes of AKI (5). Transition from the use of adaptive continuous renal replacement therapy (CRRT) equipment (6,7) to production of hemoltration machines with volumetric control allowing for accurate ultraltration ows has likewise led to a change in pediatric RRT modality prevalence patterns. Accurate ultraltration (UF) and blood ow rates are crucial for pediatric CRRT since the extracorporeal circuit volume can comprise more than 15% of a small pediatric patients total blood volume and small UF inaccuracies may represent a large percentage of a small pediatric patients total body water. Polls of United States pediatric nephrologists demonstrate increased CRRT use over peritoneal

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dialysis (PD) as the preferred modality for treating pediatric AKI (8,9). In 1995, 45% of pediatric centers ranked PD and 18% ranked CRRT as the most common modality used for initial AKI treatment. In 1999, 31% of centers chose PD vs. 36% of centers reported CRRT as their primary initial modality for AKI treatment (9). Pediatric CRRT Epidemiology As with the pediatric AKI experience, until recently, published pediatric CRRT epidemiology was limited to single center studies of generally less than 100 patients (1012), and these studies did not provide in-depth evaluations of the causes and outcomes for specic diseases states leading to CRRT provision. In 2001, the Prospective Pediatric CRRT (ppCRRT) Registry group, a multicenter Unites States collaboration, was formed to describe the current state of pediatric CRRT practice (13). The ppCRRT Registry was designed in a prospective observation format; each center followed their own local practice with respect to CRRT indications, timing, technical aspects, and termination. The Phase 1 aim of the ppCRRT Registry was to enroll 300 patients from participating centers; in May 2005, 370 patients had been enrolled and the ppCRRT Registry was closed. The demographics and clinical characteristics of the entire ppCRRT Registry 344 patient cohort with complete data (14), as well as specic subpopulations of children with MODS (15) and stem cell transplantation (16) have been published. Data from the entire ppCRRT cohort revealed 58% survival, although patients with liver failure transplant (31% survival), pulmonary disease transplant (45% survival), and stem cell transplant (45% survival) demonstrated lower survival rates. Twenty-four percent of the cohort comprised infants less than 10 kg in size, demonstrating that CRRT provision is feasible in even the smallest patients. Although smaller patients had lower survival compared to larger children (43% vs. 63%, p < 0.001), infant survival tends to be worse in the critically ill pediatric population with AKI (5). Finally, the ppCRRT cohort revealed a 35% survival rate in patients receiving CRRT for >28 days, supporting the provision of prolonged CRRT courses. A current analysis is underway to determine the clinical features that may

portend prognosis in patients receiving extended CRRT courses. Technical Considerations Access Functional vascular access is the most important technical component determining successful provision of CRRT. A wide variety of acute vascular catheters are available for the pediatric population (6,17). A recent analysis from the ppCRRT Registry demonstrated signicantly lower circuit survival rates when CRRT was delivered via: 5 and 7 French catheters, catheters placed in the femoral vs. internal jugular veins, or a convective small clearance modality (continuous veno-venous hemoltration veno-venous hemodialtration vs. continuous veno-venous hemodialysis) (17). A general acute catheter to patient size guideline is depicted in Table 1. Catheter placement for CRRT may predispose blood vessels to blood vessel sclerosis or thrombosis and may be complicated by air emboli or hemorrhage. Future permanent access in the form of an arteriovenous graft or stula for patients who develop chronic kidney disease (CKD) may be compromised if acute access is placed in a subclavian vein. Clinicians must therefore consider the potential long-term vascular needs of patients who may be expected to develop CKD. Anticoagulation Standardized protocols have been well established for both heparin and regional citrate anticoagulation. PPCRRT Registry data demonstrate heparin and citrate based anticoagulation protocols have been shown to confer equitable lter survival in pediatric CRRT, and the use of either is clearly supported over the use of no anticoagulation schemes (18). The main advantage of citrate anticoagulation is prevention of patient systemic pharmacological anticoagulation, which can be an issue in patients with multiorgan failure and sepsis. Calcium is a requisite cofactor in both the intrinsic and extrinsic coagulation cascades. Citrate functions by binding free calcium, thereby inhibiting coagulation in both the intrinsic and extrinsic coagulation pathways. The most frequently studied pediatric citrate protocol (1820) uses Anticoagulant Dextrose solution A (ACD-A, Baxter

TABLE 1. Catheter and patient size options Patient size Neonate 36 kg 630 >15 >30 >30 kg kg kg kg Catheter size and source Single-lumen 5 Fr (COOK) Dual-Lumen 7.0 French (COOK MEDCOMP) Dual-Lumen 7.0 French (COOK MEDCOMP) Triple-Lumen 7.0 Fr (MEDCOMP, ARROW) Dual-Lumen 8.0 French (KENDALL, ARROW) Dual-Lumen 9.0 French (MEDCOMP) Dual-Lumen 10.0 French (ARROW, KENDALL) Triple-Lumen 12 French (ARROW, KENDALL) Site of insertion Femoral vein Internal external-jugular, Internal external-jugular, Internal external-jugular, Internal external-jugular, Internal external-jugular, Internal external-jugular, Internal external-jugular, subclavian, subclavian, subclavian, subclavian, subclavian, subclavian, subclavian, or or or or or or or femoral femoral femoral femoral femoral femoral femoral vein vein vein vein vein vein vein

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Goldstein tive study, the mixture RRT modality with a lack of modality stratication in subject populations studied, and the inconsistent use of methods to control for patient illness severity in outcome analysis. A few studies have considered the effect of a clinical variable on outcome. Smoyer reviewed (24) the outcome of 98 infants and children with AKI who received either arteriovenous or veno-venous CRRT modalities and found a higher mortality in patients on pressors. Subsequent work (4) by Bunchman upheld this nding by showing patient survival was only 35% for those requiring pressors vs. 89% for those without a pressor requirement in the course of their AKI treatment. Few pediatric outcome studies use a standardized scoring system to control for patient illness severity, which may result from the fact that published data provide contradictory conclusions with respect to the utility of various illness severity scoring systems in predicting death in pediatric patients with AKI. Faragson demonstrated (25) signicant overlap in Pediatric Risk of Mortality (PRISM) scores (26) between surviving and nonsurviving children who received intermittent hemodialysis and therefore concluded that PRISM scores should not be used to differentiate patients who would likely or not benet from dialysis initiation. Zobel (27) demonstrated that children who received CRRT with worse illness severity by PRISM score had increased mortality, but this study included patients who received both arterio-venous and veno-venous CRRT therapies, and did not stratify by modality. More recent single center (1012) studies and one multicenter ppCRRT pediatric CRRT study (15) have used PRISM 2 score to control for illness severity at ICU admission and CRRT initiation (26). PRISM 2 does not contain a direct measure of kidney function. In all the recent studies mentioned above, the degree of uid overload at CRRT initiation has been associated with patient mortality, independent of patient severity of illness. These studies calculated uid overload by the cumulative percent uid balance (based on ICU admission weight) from ICU admission to CRRT initiation or by cumulative percent uid balance in the 7 days prior to CRRT initiation. These data, coupled with the predilection for early multiorgan system failure and death in critically ill children with AKI argue for early and aggressive initiation of CRRT. Although mean PRISM 2 scores were no different between survivors and nonsurvivors, controlling for patient illness severity using PRISM scores was essential to mitigating concerns that the patients who received more uid prior to CRRT initiation were more ill, and therefore had a higher risk of mortality. Infants Infants and neonates with AKI present unique problems for RRT provision. As noted earlier, delivery of hemodialysis or CRRT to these small patients entails a signicant portion of their blood volume to be pumped through the extracorporeal circuit. Therefore, extracorporeal circuit volumes that comprise more than 1015% of patient blood volume should be primed with whole

Healthcare, USA), prescribed based on the blood ow rate: ACD-A rate (ml/hour) blood pump rate (ml/minute * minute/hour) * 1.5 The ACD-A is infused via a stopcock at the catheter CRRT circuit connection leading to the CRRT machine. For example, a prescribed blood pump ow of 200 ml minute would result in ACD-A rate of 300 ml hour. The second aspect of the citrate protocol prevents citrate induced patient hypocalcemia by providing a calcium chloride continuous infusion (8 g calcium chloride 1 l normal saline) to the patient via a central line. The calcium chloride rate is also based on the blood pump rate: Calcium chloride (ml/hour) blood pump rate (ml/minute * minute/hour) * 0.6 Thus, the calcium chloride rate for our example would be 120 ml hour. It is important to remember that pumps independent of the CRRT machine infuse both ACD-A and calcium chloride, so the uid removal rate must account for these additional infusions. The goals of regional citrate anticoagulation are to maintain the circuit ionized calcium between 0.2 and 0.4 mm and the patients systemic ionized calcium in the normal physiologic range (1.11.3 mm). The circuit ionized calcium concentration is managed by adjustment of the citrate rate; while the patients systemic ionized calcium concentration is managed by adjustment of the calcium chloride rate. Specic Pediatric Patient Populations The Critically Ill Pediatric Patient Survival rates for critically children with AKI receiving RRT have been fairly consistent from 1978 through 2006. Overall reported patient survival ranges from 52% to 58% (3,4,10,21). In the last decade, survival rates stratied by RRT modality have also been stable; survival rates for patients receiving hemodialysis (7389%) are higher than those receiving PD (4964%) or CRRT (3458%) (4,10,22). Understanding the pattern of pediatric MODS lends insight into some of the shortcomings and strengths of pediatric AKI outcome data presented later in the article. As opposed to adults patients, Proulx (23) demonstrated that children develop severe and life-threatening MODS very early in their ICU course; 87% of children developed the maximum number of organ failures within 72 hours of ICU admission and 88.4% of deaths occurred within seven days of MODS diagnosis. Thus, methods to quickly identify children at risk of developing MODS would lead to early and aggressive initiation of supportive measures, including RRT to treat or prevent AKI sequelae, which could conceivably improve pediatric patient outcome. Unfortunately, many issues plague the pediatric AKI outcome literature, including a relative lack of prospec-

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Acknowledgments

blood to prevent hypotension and anemia. The bradykinin release syndrome (BRS) is often observed with blood priming of AN-69 CRRT circuit membranes, and is manifested by acute hypotension with CRRT initiation (28). The BRS is potentiated by the acidotic nature of the blood prime; a number of maneuvers have been reported to normalize the pH of the blood prime or bypass the blood prime of the AN-69 circuit (29,30). Another strategy involves avoidance of the AN-69 membrane in nonsepsis situations, since the main advantage of the AN-69 membrane is in superior cytokine removal characteristics. Since the prime volume is not discarded, it is important to not reinfuse the blood into the patient at the end of the treatment in order to prevent volume overload and hypertension. Continuous renal replacement therapy has been prescribed since the mid-1980s for treatment of AKI in critically ill infants (31,32). The rst CRRT modalities were arterio-venous in conguration, since the extracorporeal volumes were small in these circuits and UF was driven by patient perfusion pressure, thereby reducing the risk of hypotension from too much UF. As mentioned before, introduction of more accurate machines with volumetric control has increased veno-venous modality CRRT in pediatric patients, including neonates and infants. Zobel noted (32) that technical problems occurred only with continuous venovenous hemoltration (CVVH) in an early neonatal outcome 1991 study reporting patients who received either continuous arterio-venous hemoltration (CAVH) or CVVH. Symons reported data (33) from a more recent retrospective multicenter study evaluating the CVVH course for 90 infants less than 10 kg from 1993 through 2001, which demonstrate very few technical complications using newer CVVH machinery. Infant survival for patients receiving CRRT has also been consistent over the past decade at 3538%, which is similar to survival rates noted above for older pediatric patients (32,33), although patients less than 3 kg exhibited a trend toward worse survival (24%) when compared to infants larger than 3 kg (41%) (33). Future Studies The recent epidemiological pediatric AKI and CRRT data presented in this paper demonstrate the need and laid the groundwork for future pediatric prospective study. Since pediatric AKI is relatively rare, multicenter study is required to enroll a sufcient patient number for appropriate statistical analysis. The ppCRRT Registry initial aims to provide insight into the potential clinical factors that affect pediatric patient outcome, compare the efcacy of different anticoagulation protocols, and assess specialized patient populations including patients with metabolic disorders and bone marrow transplantation. Current and future endeavors will include assessment of CRRT pharmacokinetics, broadening the scope to include all pediatric patients with AKI and performing prospective randomized trials to evaluate the effect of CRRT dose and modality upon patient outcome.

I would express my sincere gratitude to the center PIs of the ppCRRT Registry group: Patrick Brophy, Timothy Bunchman, Douglas Blowey, James Fortenberry, Jordan Symons, Francisco Flores, Annabelle Chua, Richard Hackbarth, Mark Beneld, David Askenazi, Kevin McBryde, Michael Somers, Michelle Baum, Steven Alexander, John Mahan, and Deepa Chand and their nurse colleagues for their collaboration.

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