Continuous Renal Replacement Therapy: Current State and Future Directions for Worldwide Practice

INTRODUCTION

Continuous renal replacement therapy (CRRT) is used for management of acute kidney injury (AKI), fluid overload, intoxications, and metabolic derangements across the age spectrum. Pediatric CRRT use has increased substantially, particularly in the last decade (1, 2). Paralleling the technological developments in pediatric critical care medical practice, CRRT has quickly become an essential form of organ support in the pediatric intensive care unit (PICU). Despite its frequent and increasing use, pediatric CRRT knowledge and practice are derived from adult studies, single center pediatric reports, and a multicenter registry with selective enrollment of children from the United States that is now more than 20 years old (3). The limited nature of evidence makes it particularly challenging to identify optimal approaches that can lead to improved, and ultimately optimal, outcomes. There is insufficient practice guidance in the literature on the optimal timing of initiation, delivered dose, anticoagulation, filter type, quality monitoring and rate and quantity of fluid removal. Furthermore, standardization in practice may be hampered by small center numbers and/or variations in device and/or drug approval such as those used in anticoagulation.

Recent studies have reported outcomes of children receiving CRRT across different eras. Riley and colleagues compared outcomes of children receiving CRRT from a single center across 2 different eras (4). Despite the fact that there was significant practice change over the 10 years of study, there was no difference in survival to hospital discharge across eras (4). Goldstein and colleagues compared survival among infants treated with CRRT using adapted adult platforms versus the Carpediem™ and demonstrated an improved survival to CRRT discontinuation in those treated with Carpediem™ (5). It should be noted however, that there was nearly 20 years difference between the study period of the 2 populations and it is likely that there has been substantial improvement in medical care during the 20-year gap period of the 2 reports, independent of provision of CRRT.

In the period 2020–2023, 3 separate groups of investigators disseminated surveys and collated the results with the intent to identify CRRT practice patterns and goals for children regarding timing of initiation of support, filters commonly used, anticoagulation, dose/prescription of dialysate, fluid removal and quality monitoring (6–8), which have highlighted how significant practice varies among pediatric institutions around the world. Each of these surveys identified significant heterogeneity in practice. Indeed, these surveys have identified an important step forward in education, training, and practice for ultimately standardizing the care of children receiving CRRT. The necessity and importance of this approach was recently highlighted by the pediatric Acute Disease Quality Initiative (pADQI) expert group which provided consensus recommendations and suggestions for children receiving CRRT to ensure high-quality programs and provide a general guide for prioritizing areas of focus for future research (9). In addition, the 22^nd ADQI consensus recommendations and the accompanying pediatric responses by Harer and colleagues (10) and Selewski and colleagues (11) for improving neonatal and pediatric AKI care, respectively, provided guidance and minimum programmatic standards and quality metrics for delivering high-quality CRRT (10, 11). The purpose of this Editorial Perspective Commentary is to summarize the findings from the recent surveys and the current literature and outline a path forward to improved care and outcomes among critically ill children receiving CRRT (Table 1).

Table 1. Summary of Survey results.

CICU cardiac intensive care unit, CRRT continuous renal replacement therapy, CVVH continuous hemofiltration, CVVHD continuous hemodialysis, CVVHDF continuous hemodiafiltration, ESPNIC European Society of Pediatric and Neonatal Intensive Care, ICU intensive care unit, PICU pediatric intentive care unit, WE-ROCK Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease

	ESPNIC European Survey	Japanese PICU Survey	WE-ROCK International Survey
Demographics
Approach	Single survey	Single survey	2-round modified Delphi process survey
Participant Characteristics	ICU Medical Director of representative (one per site)	ICU Medical Director or representative (one per site)	Providers (potentially multiple per center) whose site participates in the WE-ROCK collaborative
Unit representative	Intensivists or nurses (PICU)	PICU: 22 (88.5%) CICU: 2 (7.7%) Mixed pediatric/adult ICU: 1 (3.8%)	Nephrologists and intensivists (critical care and cardiac critical care) >50% of responses in both rounds from nephrologists
Response Rate	161/283 (76%)	26/36 (72%)	147/248 (59.3%)(round 1)
Region	Europe and United Kingdom	Japan	United States (80%) Canada (10%) Europe (10%)
Managing Provider	Intensive care (77%) Nephrologist (12%)	Intensive Care (73%) Nephrologist (12%)	Intensive Care (28%) Nephrologist (62%) Both Intensive Care & Nephrology (10%)
Clinical/Prescription Characteristics
Timing of Initiation	Electrolyte derangements, uremia, fluid overload (dictated by clinical scenario)	Not reported	Based on pathologic fluid overload or inadequate urine output
Modality	CVVHDF (51%)	CVVHD (61%) CVVHDF (39%)	CVVHDF (>95%)
Dosing	35 ml/kg/hr (neonates) 30 ml/kg/hr (children)	Variable (most common 20–40ml/kg/h; range: <10, >50)	Variable (most common 2 L/hour/1.73 m2)
Anticoagulation	Heparin (41%) Citrate (35%)	Nafamostat Heparin	Variable (Citrate, heparin, prostacyclin)
Fluid removal strategy	Combined fluid balance and hemodynamic status in decision making (7%) Variability in frequency of determining fluid goals (every 4h-24h)	Not reported	Variable on timing of when removal begins, and goals.
Quality monitoring	Not reported	Not reported	>85% have a quality monitoring program
Educational Programs	No regular training on CRRT in 59%	Not reported	Not reported

SURVEYS OF CRRT

European Society of Pediatric and Neonatal Intensive Care (ESPNIC) Critical Care Nephrology section

In 2020–2022, ESPNIC conducted a cross-sectional, anonymous online survey focused on different aspects of CRRT practices in European PICUs (6). The survey targeted CRRT lead professionals from all units to avoid misdiagnosis of variation in practice based on the level of experience of health care professionals. Demographic characteristics of European PICUs along with organizational and delivery aspects of CRRT (including prescription, liberation from CRRT, and training and education) were assessed. One hundred and sixty one responses were included in the analysis for a response rate of 76% among European PICUs that performed CRRT. The attending PICU consultant (70%) and the PICU team (77%) were mainly responsible for CRRT prescription. Sixty-one percent of staff nurses received training to use CRRT, with no need for certification or recertification in 36% of PICUs. Continuous venovenous hemodiafiltration (CVVHDF) was the preferred dialytic modality (51%). Circuit priming was performed with normal saline (67%) and blood priming in children weighing less than 10 kg (56%). Median (interquartile range [IQR]) CRRT dose was 35 (30–50) mL/kg/h in neonates and 30 (30–40) mL/kg/h in children aged 1 month to 18 years. Though the Kidney Disease: Improving Global Outcomes (KDIGO) workgroup recommends regional citrate anticoagulation as the first-line anticoagulant in patients undergoing CRRT (12), 41% of PICUs used regional unfractionated heparin infusion, whereas only 35% used citrate-based regional anticoagulation. Filters were changed for filter clotting (53%) and increased transmembrane pressure (47%). For routine circuit changes, 72 hours was the cutoff in 62% of PICUs. Some PICUs (34%) monitored fluid removal goals every 4 hours, with variation from 12 hours (17%) to 24 hours (13%). Fluid removal goals ranged from 1 to 3 mL/kg/h. Clinicians used different practices for liberation from CRRT using a diuretic bolus followed by an infusion (32%) or a diuretic bolus alone (19%). Thus, this survey found a wide variation in current CRRT practice, including organizational aspects, education and training, prescription, and liberation from CRRT, in European PICUs.

Japanese PICUs

In recent years, CRRT practice in Japan has been almost exclusively limited to PICUs. Therefore, the 72% response rate for this January 2022 survey, covering all PICUs in Japan, reflects the overall practice of pediatric CRRT in Japan (8). The survey collected data on various aspects of CRRT, including institutional information, CRRT management, dialysis modalities, anticoagulation therapy, circuit exchange, drug and nutrition dosage adjustment, and rehabilitation during CRRT.

The results showed that treatment plans were often chosen at the discretion of the physician in charge, rather than following manuals or practice guidelines. CRRT was mostly managed by intensivists (73%), and only a few were managed by nephrologists (12%). The most common CRRT mode for AKI was continuous venovenous hemodialysis (CVVHD), used in 62% of the institutions, followed by CVVHDF, used in 38% of the institutions. The most common maintenance dose for AKI was 20–29 ml/kg/h (39%), followed by 30–39 ml/kg/h (15%) and >50 ml/kg/h (12%). Nafamostat mesylate was the primary anticoagulant used, with unfractionated heparin also being commonly employed. The frequency of circuit exchange varied among institutions, and drug and nutrition dosages were adjusted differently depending on the institution. Rehabilitation was actively implemented in many institutions during CRRT.

The Worldwide Exploration of Renal Outcomes Collaborative in Kidney Diseases (WE-ROCK) International collaborative

A systematic review of the 2012–2022 literature informed two-rounds of a survey sent in 2022 to CRRT prescribers participating in the WE-ROCK collaborative (7), which comprises 32 centers from around the world (13). A modified Delphi approach was used whereby consensus was defined by a ≥75% participant response of “sometimes” or “always” in the 63 and 50 item, first and second rounds of a survey, respectively. Importantly, although the survey was sent to CRRT prescribers in eight countries, the majority of respondents were from the United States (80%). This survey did evaluate respondent use of quality monitoring during CRRT. Although 86% of respondents provided a response of “always” or “sometimes” quality monitoring, there was a wide range of responses regarding methods used to monitor dose delivered.

There was variability among survey participants regarding CRRT timing of initiation, dosing, and anticoagulation practices. Although criteria for consensus was met regarding possible percent fluid balance and urine output thresholds for guiding CRRT initiation, a response of “always” ranged from 4–41% for the practices surveyed on the first round. There was no consensus on serum creatinine-based thresholds for which to start CRRT. The majority of participants indicated that they “always” or “sometimes” prescribe dialytic dose based on body surface area (78%), aim for a clearance of 2 L/hour/1.73 m² when dosing based on body surface area (98%), or use CVVHDF as a primary mode of therapy (97%). There was variability in where prescribers administer replacement fluid when performing continuous venovenous hemofiltration (CVVH). Although the majority of prescribers indicated that they use citrate or heparin as an anticoagulant on CRRT, there was a wide range of responses regarding anticoagulation monitoring parameters.

DISCUSSION

The three contemporaneous distinct surveys from three geographical regions highlight the shift in pediatric CRRT practices that has happened over the last two decades, with a major focus in the emerging field of pediatric critical care nephrology. It is clear that evolving practices in pediatric CRRT are influenced by regional practice patterns. However, even within the same region, heterogeneity exists among prescribers.

Clinical practice and technical innovation in pediatric CRRT care have outpaced the systematic generation of robust evidence supporting differing approaches to timing, dose, modality, pace of fluid removal, and liberation. Miniatuarized devices are revolutionizing the dialytic care of newborns and infants (14–16). Given lack of evidence delineating individual approaches associated with improved patient outcomes, testing a best practice approach against usual care is unlikely to be feasible, as there are simply too many unknowns. Understanding drivers of heterogeneity in practice and exploring associations with distinct patient-centered outcomes are necessary to inform future innovations and improvements in pediatric CRRT practice.

While the heterogeneity in practice might be leveraged to directly compare certain aspects of real-world pediatric CRRT practice, such as type of anticoagulation or modality, this would require funding agencies to support international collaboratives, such as WE-ROCK, as these varied practices exist in different regions. Support and endorsement by relevant professional societies would bolster international collaborative efforts. As AKI is common and CRRT is a sine qua non of the PICU organ support toolbox, maximizing innovative embedded approaches to adequately depict clinically generated dense and frequent data in the particularly data-rich environment of the PICU is necessary. The continuous and dynamic nature of CRRT provision needs to be captured adequately. Use of data archiving platforms and integration of devices into electronic medical records might facilitate appropriate data acquisition as manual data collection is simply not feasible. Standardization of nomenclature, paralleling the efforts already underway in adult critical care nephrology, would facilitate these efforts (17). In addition, consensus needs to be built with the inclusion of patient and family representatives on a meaningful core outcome set as it has been done in chronic dialysis and general critical illness (18, 19).

Diversity in practice may be unavoidable given regional availability of durable medical equipment and medications (20). Despite the importance of the three surveys, all of them lack sufficient granularity to get a true scope of practice patterns in all PICUs and other pediatric ICUs utilizing CRRT, making it especially challenging to identify which practice pattern is likely to be associated with the best outcome. Efforts that span across the world with an understanding of local resources are necessary to implement the lessons learned from a pragmatic reality (21). Indeed, even among adult practice, there is significant heterogeneity in practice and outcome definitions (22), and dissecting each nuance of practice may be necessary to gain a deeper insight to practice patterns and associated outcomes (23). While it may be impossible to standardize delivery of care, Larsson and colleagues propose a framework for understanding value-based healthcare in order to transform health care organizations, focusing on outcomes that are important to the patient (24). They describe the goals of the framework including the development of public policies, regulations and shared infrastructure to encourage multi-stakeholder cooperation and value-based innovation across the global health care industry (Figure 1). This would allow for the development of dynamic ecosystems that deliver high value care. In order to accomplish this, the authors define 3 necessary and major tasks for success: 1) systematic collection and sharing of comprehensive data on patient centered health outcomes on a global scale; 2) aligned initiatives in the domain of value-based payments with continuous improvement in health outcomes; and 3) investment in the creation of digital standards and open platforms that will transform health care into learning systems. Despite the fact that researchers have been able to leverage the growth in the availability of health outcomes and other health related data to conduct prospective, pragmatic, randomized controlled trials that evaluate the effectiveness of clinical interventions, allowing for real-time comparative research, more rapid updating of clinical guidelines and more effective monitoring of compliance, these initiatives have been somewhat fragmented and uneven across countries and medical conditions. Unfortunately, kidney focused initiatives approximate the goals mentioned in the article by Larsson and colleagues are limited in adult critical care nephrology and completely absent in children. Thus, moving forward, this should be a priority.

Figure 1.

CONCLUSION

Heterogeneity in practice, regional limitations in medications and durable medical equipment, and the absence of platforms that allow for uniform data collection and systematic assessment of patient centered outcomes have, and will continue to hamper standardized care, particularly among children receiving CRRT. The multidisciplinary, multinational collaboratives such as WE-ROCK, the Critical Care Nephrology Section of ESPNIC, and others that are being developed are steps in the right direction. Patient and family important outcomes, both kidney function related and global, need to be identified with adequate stakeholder representation and continuation. Core outcomes and standardized nomenclature would facilitate pragmatic research platforms that optimally leverage clinical data collection for creation of true learning healthcare systems that maximize value-based healthcare (Table 2).

Table 2. Knowledge gaps for building global consensus in pediatric continuous renal replacement therapy (CRRT).

PIRRT, prolonged intermittent renal replacement therapy

Gaps in knowledge for building global consensus in pediatric CRRT practice

Ideal CRRT team composition Standardized nomenclature Timing of initiation Modality impact on outcomes Dosing (delivered vs prescribed) Anticoagulation (systemic vs regional) Fluid removal strategy – timing and rate of fluid removal Liberation timing and use of PIRRT Long term renal and global outcomes of CRRT survivors Quality programs and key performance indicators Minimum data set required for pediatric CRRT trials Frequency and format of regular training for maintaining critical competence Onboarding new users