Efficacy and Mechanism Evaluation (Jan 2024)
Evaluation of efficacy, outcomes and safety of infant haemodialysis and ultrafiltration in clinical use: I-KID a stepped wedge cluster RCT
Abstract
Abstract Background Critically unwell babies in intensive care units may develop acute renal failure. Options for renal replacement therapy are limited by their small size and available technology. Objectives To determine the clinical efficacy, outcomes and safety profile of the NIDUS® (a novel infant haemodialysis device) for babies under 8 kg, compared with current renal replacement therapy. Design A clinical investigation using a non-blinded cluster stepped wedge design with paediatric intensive care units randomised to sequences. Setting Paediatric intensive care units in six UK hospitals. Participants Children under 8 kg who required renal replacement therapy for fluid overload or biochemical disturbance. Interventions Continuous renal replacement therapy was provided by the usual methods: peritoneal dialysis and continuous haemofiltration (during control periods) and by the NIDUS (during intervention periods), a novel device designed for babies with a smaller circuit and filter and volumetric control of ultrafiltration. Main outcome measures Primary outcome was precision of ultrafiltration compared with prescription; secondary outcomes included biochemical clearances, accuracy of reported ultrafiltration and mortality. Data sources Bedside study data collected by weighing bags of fluid entering and leaving the device were entered into the study database along with case descriptors. Some secondary outcome data was collected via the Paediatric Intensive Care Audit Network. Results Ninety-seven participants were recruited by study closure, 62 to control and 35 to intervention. The primary outcome was obtained from 62 control but only 21 intervention patients, largely because of technical difficulties using NIDUS. The analysis comparing the available primary outcomes showed that ultrafiltration with NIDUS was closer to that prescribed than with control: standard deviations controls 18.75, intervention 2.95 (ml/hour), adjusted ratio 0.13, 95% confidence interval (0.03 to 0.71); p = 0.018. The mean clearances for creatinine, urea and phosphate were lower on peritoneal dialysis than NIDUS, which were in turn lower than continuous veno-venous haemofiltration. The variability in the clearances was in the same order. Of the 62 control patients, 10 died (2/62 on peritoneal dialysis; 7/13 on continuous haemofiltration) before discharge from paediatric intensive care unit (16%), compared with 12 out of 35 (34%) in the NIDUS group: p = 0.04, 95% confidence interval for difference (0 to 36%). Harms No important adverse events occurred and the NIDUS has an acceptable safety profile compared with other renal replacement therapies in this critically ill population with multi-organ failure. Mortality was lowest for Peritoneal Dialysis, highest for continuous haemofiltration, with the NIDUS in-between. Only one serious adverse device event which was reported to the Medicines and Healthcare products Regulatory Agency. Conclusions NIDUS works effectively, delivering appropriate blood clearances and accurate, controllable fluid removal (ultrafiltration), indicating that it has an important place alongside other dialysis modalities for infant renal replacement therapy. Future work Findings from this study indicate some modifications are required to NIDUS to improve usability. Further studies on use of the NIDUS device in other populations of babies for example those with chronic renal failure, and long-term outcomes are required. Trial registration This trial is registered as ISRCTN 13787486. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 14/23/26) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 1. See the NIHR Funding and Awards website for further award information. Plain language summary Why do this study? Some children in intensive care are so poorly that their kidneys do not work well, and they need help, called dialysis, to get rid of fluid and chemicals from their blood. For babies, we currently use peritoneal dialysis, where fluid is cycled in and out of the tummy, or adapted machines designed for bigger children (continuous veno-venous haemofiltration). A new machine, the NIDUS® (Allmed, www.allmedgroup.com), was developed specifically for babies weighing under 8 kg with much smaller tubing. NIDUS worked well when studied in Newcastle but needed testing elsewhere. What was the question? How well does NIDUS work compared to other dialysis methods? What are the problems? What did we do? The study was done in six paediatric intensive care units who used their usual dialysis methods (=control) in the first part of the study and then later swapped to using the NIDUS (=intervention). What did we find? We recruited 97 participants, 62 to control (49 peritoneal dialysis, 13 continuous veno-venous haemofiltration) and 35 intervention (NIDUS). We found NIDUS provided much better control of fluid removal. The CVVH machines were more efficient at blood cleaning than NIDUS, which was better than peritoneal dialysis. What does this mean? We learnt a lot about babies needing kidney support in paediatric intensive care units and that all methods have advantages and disadvantages. We showed that NIDUS could be very useful for some participants because it cleans blood effectively and gives accurate, controllable fluid removal. We have gathered important information to help us improve NIDUS to make it easier to use and run. Many parents responded to our questionnaire and most told us they felt it was acceptable to be approached about taking part in research despite the circumstances. This is very important for future research studies. We are very grateful to families for their generosity in becoming involved in this study. Scientific summary Background Critically unwell babies in paediatric intensive care units (PICUs) may develop acute renal failure and require management with renal replacement therapy. Although mortality and morbidity vary and are related to the underlying diagnosis, survival of babies in paediatric intensive care is worse for those with fluid overload. Babies requiring renal replacement treatment present specific therapeutic challenges because of their small size and the current technology available. Difficulties with vascular access and blood flows, fluid balance, loss of circuits, filter clotting and hypotensive episodes at initiation are all described in the literature. The need for new solutions and improved technology is well recognised. Continuous veno-venous haemofiltration (CVVH) machines in use in the UK at the time of this study are not approved for use in babies weighing 80%) were similar. The median (IQR) age in controls 10.5 (7, 38) days was similar to that in the intervention group 11 (7, 61) days; the range of age of participants was between 1 and 477 days (approximately 15 months). The median (IQR) weights 3.2 (2.9, 3.9) and 3.7 (3.1, 5.6) kg were similar between control and intervention. Availability of primary outcome The primary outcome was available on all 62 control patients but only 21 of the 35 intervention patients. This was due to a range of reasons including difficulties in obtaining the information needed to compute the UF rate (accurate timing and weighing data) and technical difficulties using the NIDUS: full details are in the report. Precision of UF Analysis comparing the 62 control patients with the 21 intervention patients with a primary outcome showed that UF with the NIDUS was closer to that prescribed than with control: standard deviations (SDs) controls 18.75, intervention 2.95 (ml/hour), adjusted ratio 0.13, 95% confidence interval (0.03 to 0.71); p = 0.018. For the NIDUS and CVVH devices, an important measure was to compare the difference between the actual fluid removal measured and that reported by the device. This had a mean closer to zero for the NIDUS than CVVH (means −0.44 vs. 11.6 ml/hour, respectively), with less variation in NIDUS than CVVH (SDs 3.2 vs. 28.4 ml/hour). Biochemical clearances The initial intention was to compare clearance rate on NIDUS with the control group. However, for these variables combining PD and CVVH in this way proved to be misleading because NIDUS clearances rates were intermediate between those of PD and CVVH. The clearance for creatinine on PD was smaller and less variable (mean 0.08, SD 0.03 ml/min/kg) than on the NIDUS (mean 0.46, SD 0.30 ml/min/kg), which was in turn smaller and less variable than for CVVH (mean 1.20, SD 0.72 ml/min/kg). The pattern was repeated for urea: PD (0.12, 0.06), NIDUS (0.48, 0.30) and CVVH (1.15, 0.67), all in ml/min/kg, and also for phosphate: PD (0.07, 0.04), NIDUS (0.44, 0.27) and CVVH (1.16, 0.71), all in ml/min/kg. All pairwise treatment comparisons of means and of SDs gave p < 0.001. More detail on the UF and clearances are provided in the results section of the main report. Survival Of the 62 participants receiving control treatment, 54 survived to 30 days (87%) and 52 (84%) survived until discharge. For the 35 participants in the NIDUS group, 25 survived to 30 days (71%) and 23 (66%) survived to discharge. For the participants receiving PD 47 of 48 participants (98%) survived to 30 days, and 46 (96%) survived to discharge, whereas for the 13 participants on CVVH the corresponding values were 7 (54%) and 6 (46%). The participant receiving ECMO plus haemodialysis is not included in these figures. Exposure to blood transfusion while on renal replacement treatment Median (IQR) haemoglobin concentrations prior to starting renal replacement treatment were similar. However, only 7 (15%) of the participants on PD required a blood transfusion, whereas 12 (92%) of the 13 on CVVH required blood transfusion and 27 (77%) of those on NIDUS required blood transfusion. Five of the ten babies, whose CVVH circuits were via conventional central venous access lines, required priming with blood rather than saline, but none of the NIDUS circuits needed this. Use of inotropes or fluid bolus Hundred per cent of participants on PD, seventy-seven per cent of those on CVVH and eighty-nine per cent of those on NIDUS were reported as receiving additional fluid bolus (defined as 80 ml/kg by the PICANet) or inotropes infusion in the first 48 hours of renal replacement treatment. Safety reporting There were 27 adverse events (AEs) across 23 participants (15 control, 8 intervention). Adverse device events were only reported for the NIDUS intervention. There was one adverse device event which was possibly related to the NIDUS device/tubing set. There were 17 serious adverse events across 15 participants (8 control, 7 intervention). One serious adverse device event was reported throughout the study. Conclusions The I-KID study provides important new information about renal replacement treatment in babies on PICUs. The results show that the UF obtained with the NIDUS was closer to that prescribed than with control. Moreover, the UF reported by the NIDUS was a reliable reflection of the true UF. Clinically both aspects are important. While measurement of UF with PD is easy and accurate, the uncontrollability and unpredictability of UF is clinically recognised as an issue. It is also very important to be able to rely on the information given by a dialysis/filtration device being accurate for the clinician to make appropriate adjustments to the patient’s overall fluid balance. Conversely, if the device gives inaccurate information to the clinical team it contributes to uncertainty and difficulty in overall fluid management. Manufacturers are aware of the inherent imprecision of their devices and give warnings in their technical documentation and indeed, concern regarding variability in fluid removal was the initial reason for licensing restriction of CVVH devices. There is currently only one device licensed for babies under 8 kg, the Cardio-Renal Pediatric Dialysis Emergency Machine (CARPEDIEM®) (Medtronic, www.medtronic.com), which was not in use in the UK during this study time and was not available for study in I-KID. The clearance comparison between PD and NIDUS reflects that found in a previous study, whereas this is the first comparison between CVVH (Prismaflex® and Aquarius®) and NIDUS. Given the greater blood flow and larger filter surface area of the CVVH devices, these results are as anticipated. Clinically, the NIDUS would provide adequate biochemical clearance for controlling biochemical disturbance in babies with acute renal failure. Many babies requiring renal replacement treatment in PICUs are critically unwell, as reflected by the vast majority of participants in I-KID having multi-organ failure; most were on positive pressure ventilatory support. There was a very high use of inotrope infusions, but it is unclear whether this was largely ‘routine use’ in babies postoperatively after cardiac surgery or related to hypotensive episodes. The survival data reflects the high mortality associated with the underlying clinical diagnoses. Mortality was lowest for PD and highest for CVVH, with NIDUS in between. Babies who are unwell and particularly post surgical may require blood transfusion for a number of different reasons. Few babies on PD required blood transfusion but rates were much higher in babies treated with CVVH and NIDUS. Those participants may have been more unwell or the process of haemofiltration and dialysis renal replacement treatment increases the need for blood transfusion. Half of the CVVH circuits connected to the babies’ central venous lines required blood priming, but none of the NIDUS circuits did. Recruitment was high in the first part of the study, when most participants were entering the control phase, but was less good as the study progressed and sites were mainly enrolling babies into the intervention phase. The study faced a number of challenges to delivery, including moratoria on non-COVID-19 research during the early phases of the COVID pandemic. The number of control cases on PD (vs. CVVH) was higher than we had estimated. There were AEs reported in both control subgroups and in intervention cases. NIDUS was shown to have an acceptable safety profile compared with other modalities used in this critically unwell population. Implications for health care The I-KID study had high input from public and parents at all stages from the early development phase onwards and this was crucial to ensuring acceptability to participant parents. Importantly, most parents who responded to the questionnaire indicated they felt it was acceptable to be approached about taking part in research despite the circumstances. This is important for future research studies in critical care. The study required and achieved a high degree of support from clinicians and nursing staff. An important safety profile has been created and user feedback from I-KID has provided vital information on improvements required to NIDUS to improve usability. Peritoneal dialysis is likely to remain a commonly used technique for babies with less severe renal failure who require less intensive dialysis. Many postoperative babies (especially those undergoing cardiac surgery) have a PD catheter inserted during surgery, which is sometimes just used for draining ascitic fluid and can be easily used for dialysis if required. However, insertion of a PD catheter is not without its risks, and there is room for future studies questioning the best immediate postoperative renal support modality. Where PD is not possible or fails, it is clear that NIDUS provides a good therapeutic option to be considered. Largely the results were in concordance with clinical experience of renal replacement treatment in babies and with previous NIDUS animal and compassionate use reports. The results show that the intervention device, NIDUS, works effectively delivering appropriate blood clearances and accurate, controllable fluid removal (UF), with an appropriate safety profile, indicating that it has an important place alongside other dialysis modalities in the management of babies with renal failure. Trial registration This trial is registered as ISRCTN 13787486. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 14/23/26) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 1. See the NIHR Funding and Awards website for further award information.
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