Title: I-KID ( Infant KIdney Dialysis and ultrafiltration) :evaluation of efficacy, outcomes and safety of infant haemodialysis and ultrafiltration in clinical use
Funder: Department of Health and Social Care

Abstract: Survival of babies in Paediatric Intensive Care (PICU) is only 50-75% for those requiring renal replacement therapy (RRT) for fluid overload or acute kidney failure [1,2]. RRT is supportive until renal recovery but up to 30% may have chronic kidney sequelae. Until this year [16]there were no approved devices for continuous haemofiltration (CVVH) for children under 8kg and many reports of safety concerns. Currently clinicians have to use machines outside recommendations, or use peritoneal dialysis (PD), for approximately 300 infants under 8kg, in UK PICUs, who need RRT each year. RRT in infants is associated with adverse events including haemodynamic instability [3]. The Newcastle infant dialysis and ultrafiltration system (Nidus) is the first device designed for babies 0.8 to 8kg, and has been shown to be efficacious in a pilot study [4]. Further data on efficacy and safety in clinical use outside the development centre are urgently needed. The aim of this study is to compare Nidus with conventional RRT in PICU. Our hypothesis is that fluid balance control and clinical outcomes will be superior in babies treated with the Nidus with good blood clearance and fewer adverse events. We propose a randomised, stepped wedge cluster design: a one-way cross over with each unit acting as their own control. This was chosen over individual patient randomisation because of the strong views of parents, public and professionals regarding feasibility, recruitment, equipoise, ethics, training and safety in this specific PICU situation. The population is babies under 8kg needing continuous RRT for renal impairment or fluid overload in PICU. The intervention is Nidus, compared to current RRT either PD or CVVH (control). The primary outcome is precision of fluid removal. Secondary outcomes include survival, ventilator-free days, renal recovery, biochemical clearances, haemodynamic status (drop in BP requiring intervention) and adverse events such as transfusions, unplanned loss of circuits and access line changes. In addition, and strongly supported by parents, public and professionals, there will be availability of compassionate use for babies under 8kg outside PICU who fail conventional dialysis treatment and for whom there is no other option. Views of staff on acceptability and usability and experience of parents will be sought by questionnaire and a safety profile of the Nidus will be produced. Assessments include accurate fluid measurements, routine biochemical analyses and clinical observations. In a 36 month study, we plan to recruit 100 babies from 5 centres. This is feasible based on detailed analysis of current UK audit data (PICANet). Recruitment rate is likely to be high as there is potential for direct patient benefit, current CVVH devices are non-approved, and consent is for data collection and use. For the study, Nidus will be loaned and consumables cost is comparable. We predict a reduction in additional treatment costs and morbidity from blood transfusion and adverse events. The trial is designed to have 80% power to detect a three fold increase in the precision of the assessment of UF: data will be analysed using a generalized estimating equation. The experienced multi-centre team have the full breadth of expertise to deliver this project. It provides good value for money as the intervention will have direct effect on clinical care of NHS patients and results will be applicable to babies under 8kg in other PICUs worldwide.

Lay abstract: Kidneys remove waste products and excess water from the body by making urine. If they stop working, various types of dialysis can be used: peritoneal dialysis (PD) where fluid is cycled in and out of the abdomen, and haemodialysis (HD) where blood is removed by a machine and cleaned as it passes through a dialysis circuit. These are called renal replacement therapy (RRT). In paediatric intensive care units (PICU) RRT is required for babies who are so unwell that their kidneys are temporarily not working well. Babies born with abnormal kidneys may also depend upon RRT. Small babies on RRT are often very sick and tend to stay longer in PICU, need more ventilator (breathing) support and a quarter to half die. Up to a third of those who survive can have some long-term kidney problems. Using the existing RRT methods in PICU, we commonly face problems treating the smallest babies (under 8kg), of which there are about 300 each year in the UK. PD has limited ability to clean blood and remove fluid and is prone to complications like leaking, blockage, and infection. There are no HD machines approved for use in babies under 8 kg as they are not sufficiently precise but as there may be no alternative medical teams often try a continuous form of HD called CVVH. This cleans blood well, but requires a large volume of blood (60ml) to be removed from the baby into the circuit and thus for safety, blood is often used to pre-fill the circuits. The machines are inaccurate in fluid removal by about 30mls per hour (so a machine set to remove 30mls per hour may remove 0mls or 60mls). This is a problem in the smallest babies who can quickly become dehydrated or overloaded. Because of these problems, we have developed a new machine, the Newcastle infant dialysis and ultrafiltration system (Nidus) especially for infants weighing 800g -8 kg. So far, in a pilot study we have shown that it works much better than PD. The Nidus needs a smaller blood line, operates at lower blood flows, and its 10 ml circuit means that blood pre-filling is not needed. It is easy to use and its fluid removal is very precise. To compare current RRT with the Nidus, we will study about 100 babies who are dialysed in PICUs in 5 centres across the UK. Each unit will monitor infants on current RRT for a period, then the NIDUS will be introduced instead, so the difference in their performance can be compared. The units will make this change over 1 year, in sequence , which is called a cluster stepped-wedge design. Parents and a public research forum have welcomed this approach because the parents of very ill children will not have to choose between different dialysis machines at a moment of great stress; their child will be treated with the type of dialysis being routinely used at the time, and they will be asked to decide if they want their child's data included in the study analysis. We will measure if the Nidus provides better fluid control, and monitor other advantages or disadvantages. We will also evaluate the outcomes of babies who have been treated with the Nidus as “rescue therapy” when other dialysis options have failed or are not possible. An important assessment will be to seek the parents' and nurses' views. The study team of experienced researchers and a parent whose child was in the pilot study, are working closely with the Nidus manufacturers. The study will be good value for money, with most costs being for staff and training, as treatments are similarly priced.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: RENAL AND UROGENITAL