Discussion
STEC infection, STEC infections, hyperhydration, STEC, kidney injury, AKI, HUS
RECRUITMENT, COMPLICATIONS
The HIKO STEC trial is an embedded, cluster-randomized, crossover trial that will enroll 1040 STEC-infected children to test the hypothesis that hyperhydration is nephroprotective, improves outcomes, and reduces complications when compared to traditional conservative fluid management. This trial is important because HUS develops in up to 20% of children with high-risk STEC infections children and 60% of these children will require RRT. Thus, although STEC infection is one of the most common causes of acquired kidney injury in young children [This trial is required because equipoise remains regarding use of hyperhydration in STEC-infected children, particularly in the pre/early-HUS time periods. A cluster-randomized crossover design avoids the logistical issues associated with patient-level randomization given our anticipated timelines, approach to participant identification and recruitment, the multitude of physicians and clinical services involved, and the many locations (e.g., home, emergency department, inpatient) involved in patient care. Thus, after extensive consultation, and in consideration of recommendations provided by grant peer-reviewers, it was concluded that alternating between treatment options at an individual patient level within an institution would be too disruptive and confusing. By implementing a cluster-crossover trial design, the intervention is bundled into clinical care, and families can be at home when the conservative fluid management protocol is initiated. This approach minimizes the burden on families which would be significant in an individual patient-level randomized trial, as treatment would be unpredictable and would require all children to be recruited and consented for care at any time of the day. It would also require that they travel to the study site without knowledge of their treatment plan (e.g., outpatient or inpatient) until their child is randomized. This embedded, pragmatic approach, with research consent required for data and biospecimen collection, is similar to and builds on other NIH-funded trials such as TiME [Our design is pragmatic; by embedding the allocated treatment pathway into clinical care [Participating sites (Fig. To minimize bias, we will adhere to the guidelines on the conduct of cluster randomized crossover trials [We have designed this study cognizant of the difficulties inherent to trials of fluid treatment strategies. The categorical assignment of such interventions is complicated by clinical realities including variable and at times severe clinical courses, interval since illness onset, and physician awareness and preferences as it relates to intravenous fluid administration in children with evolving AKI. These factors may generate a range of fluid administration in both arms and the potential for intervention overlap. Nonetheless, the volumes we propose were chosen to encompass the continuum of fluid administered to STEC-infected children in multiple continents (e.g., North America [