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 <8 kg (<20 kg in the USA), but because of lack of alternatives, they are frequently used by clinicians outside of licence and recommendations. Objectives The objectives of the I-KID study were to determine the clinical efficacy, outcomes and safety profile of a novel non-CE marked infant haemodialysis (HD) device for babies under 8 kg: the NIDUS® (Allmed, www.allmedgroup.com) compared to current renal replacement treatment. Methods The study used a cluster-randomised standard stepped wedge (SW) design with 4 periods and 3 sequences, hence 12 treatment cells. The clusters were PICUs. Conventional therapy [peritoneal dialysis (PD) or CVVH] was used in the control cells, with the NIDUS used in the intervention cells. Each site was trained in setting up and using the NIDUS before switching to an intervention period. The design meant that all participating centres had the chance to use both treatments during the course of the study. PICU nurses were competency-assessed before each site could begin using the intervention; 24-hour on-call nurse/clinician telephone support was provided from Newcastle. Using a SW design permitted phased training on the NIDUS and allowed within-centre comparisons to contribute to the treatment estimate. The setting was PICUs in six hospitals in the UK, chosen because of their experience of performing renal replacement treatment in babies, and willingness to collaborate. Informed consent was sought from parents/guardians of children weighing from 800 g to 8 kg who required renal replacement treatment for fluid overload or biochemical disturbance (babies with suspected inborn errors of metabolism, for example leading to hyperammonaemia were excluded). Because of the urgency of requirement to start renal replacement treatment in some cases, where necessary, deferred consent was sought as soon as possible. Interventions During control periods, renal replacement treatment was provided by the usual methods in each PICU: PD and CVVH and, after a period of training and competency assessment, by the NIDUS during intervention periods. In addition, one infant being treated on an extracorporeal membrane oxygenation circuit during the control period had renal replacement treatment added by the integration of a HD filter inserted into that circuit. There was no blinding. Outcome measures Primary outcome The first observation of precision of fluid removal [ultrafiltration (UF)] from an episode lasting at least one hour for CVVH or the NIDUS, or at least 5 hours for PD within 48 hours of the start of renal replacement treatment. Secondary outcomes (related to the primary outcome) average of all precision values observed on the patient biochemical clearance rates for creatinine, urea and phosphate precision of observed versus reported fluid removal (CVVH and NIDUS only). Other secondary outcomes survival haemodynamic status (drop in blood pressure after connection to CVVH or dialysis device, requiring intervention of fluid bolus or administration of inotropes) number of ventilator-free days during renal replacement treatment completion of intended renal replacement treatment course need for additional vascular or dialysis access unplanned change in circuits exposure to blood transfusion bleeding events anticoagulant use. Secondary outcomes from questionnaires parent/guardian experience staff acceptability and usability of device. Data sources Data were collected on UF by timed weighing of fluid delivery and output bags used by the CVVH (Prismaflex® and Aquarius®) and NIDUS. For PD using manual circuits, volumes delivered and removed were measured by the bedside nurse. Timed UF and blood samples were performed to calculate biochemical clearances. Bedside study data were entered into a bespoke study database along with case descriptors. Some secondary outcome data were collected via the Paediatric Intensive Care Audit Network (PICANet), as this was already established in use at study sites. Results The planned sample size was 95 participants. By study closure 97 participants were recruited, 62 to control and 35 to intervention. Descriptive summaries were similar in both control and intervention groups; around half the participants had unplanned admissions to paediatric intensive care and approximately a third were transferred from outside hospitals. Renal replacement treatment was required post surgery in 52% of control and 40% of intervention cases. For those requiring renal replacement treatment post surgery this involved cardiac bypass surgery in 97% of controls and 84% of intervention participants. Systolic blood pressure, median [interquartile range (IQR)] control 68 (59, 78), intervention 68 (60, 86) mmHg and need for mechanical ventilation (>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.

Objectives:Renal replacement therapy (RRT) options are limited for small babies because of lack of available technology. We investigated the precision of ultrafiltration, biochemical clearances, clinical efficacy, outcomes, and safety profile for a novel non-Conformite Europeenne-marked hemodialysis device for babies under 8 kg, the Newcastle Infant Dialysis Ultrafiltration System (NIDUS), compared with the current options of peritoneal dialysis (PD) or continuous venovenous hemofiltration (CVVH). Design:Nonblinded cluster-randomized cross-sectional stepped-wedge design with four periods, three sequences, and two clusters per sequence. Setting:Clusters were six U.K. PICUs. Patients:Babies less than 8 kg requiring RRT for fluid overload or biochemical disturbance. Interventions:In controls, RRT was delivered by PD or CVVH, and in interventions, NIDUS was used. The primary outcome was precision of ultrafiltration compared with prescription; secondary outcomes included biochemical clearances. Measurements and Main Results:At closure, 97 participants were recruited from the six PICUs (62 control and 35 intervention). The primary outcome, obtained from 62 control and 21 intervention patients, showed that ultrafiltration with NIDUS was closer to that prescribed than with control: sd controls, 18.75, intervention, 2.95 (mL/hr); adjusted ratio, 0.13; 95% CI, 0.03-0.71; p = 0.018. Creatinine clearance was smallest and least variable for PD (mean, sd) = (0.08, 0.03) mL/min/kg, larger for NIDUS (0.46, 0.30), and largest for CVVH (1.20, 0.72). Adverse events were reported in all groups. In this critically ill population with multiple organ failure, mortality was lowest for PD and highest for CVVH, with NIDUS in between. Conclusions:NIDUS delivers accurate, controllable fluid removal and adequate clearances, indicating that it has important potential alongside other modalities for infant RRT.

Aims & Objectives: Paediatric index of mortality (PIM) score is a widely-used severity scoring system used to predict outcomes of patients admitted to paediatric intensive care units, and to monitor the quality of intensive care. In the UK, preterm neonates may be admitted to paediatric intensive care units. The PIM score is calibrated for necrotising enterocolitis but not for prematurity. We hypothesize that PIM score performance will deteriorate with increasing prematurity. Methods There were 1490 admissions to our unit over 10 years (2006–16) with gestational age between 23 and 37 weeks on admission. They were grouped according to gestational age (23–26 weeks N=81, 27–30 weeks N=399, 31–34 weeks N=579, 35–37 weeks N=431) and the standardised mortality ratio (SMR) was calculated for each group (SMR=Observed deaths/Expected deaths). Results The SMRs with 95% confidence intervals for each group are represented in table 1.More deaths than expected occurred amongst the patients admitted with gestational age 31–34 weeks (95% confidence interval 1.07 – 1.73). SMR for the other groups lie within the 95% confidence interval. Conclusions The PIM score may underestimate morality for preterm neonates admitted to a UK PICU with a gestational age of 31–34 weeks. Our analysis does not support the hypothesis that PIM score performs increasingly poorly with increasing prematurity. However, the numbers of patients in each group remains small and the data was taken from a single UK center. Confirming this observation is important in order for ICUs that admit preterm children to confidently use PIM scoring to assess their performance.

PURPOSE:Paracetamol has been associated with a reduction in blood pressure, especially in febrile, critically-ill adults. We hypothesised that blood pressure would fall following administration of paracetamol in critically-ill children and this effect would be greater during fever and among children with a high body surface area to weight ratio. METHODS:A 12-month prospective observational study of children (0-16years) admitted to paediatric intensive care, who underwent pulse contour analysis and received paracetamol concurrently. RESULTS:Mean arterial blood pressure decreased significantly by 4.7% from baseline (95% CI 1.75-8.07%) in 31 children following 148 doses of paracetamol. The nadir was 2-hour post-dose. The effect was pronounced in children with fever at baseline (6.4%, 95% CI 2.8-10%), although this was not statistically significant. There was no simple relationship between this effect and body surface area to weight ratio. The association between a change in blood pressure and changes in heart rate or measured stroke volume was poor; therefore it was likely that a change in the systemic vascular resistance contributes most to this effect. CONCLUSION:There is a significant but modest reduction in blood pressure post-paracetamol in critically-ill children. This is likely related to a change in systemic vascular resistance.

The role played by fever in the outcome of critical illness in children is unclear. This survey of medical and nursing staff in 35 paediatric intensive care units and transport teams in the United Kingdom and Ireland established attitudes towards the management of children with fever. Four hundred sixty-two medical and nursing staff responded to a web-based survey request. Respondents answered eight questions regarding thresholds for temperature control in usual clinical practice, indications for paracetamol use, and readiness to participate in a clinical trial of permissive temperature control. The median reported threshold for treating fever in clinical practice was 38 °C (IQR 38–38.5 °C). Paracetamol was reported to be used as an analgesic and antipyretic but also for non-specific comfort indications. There was a widespread support for a clinical trial of a permissive versus a conservative approach to fever in paediatric intensive care units. Within a trial, 58% of the respondents considered a temperature of 39 °C acceptable without treatment.

Tom Brick and Christine Pierce describe a successful new programme in the intensive care unit at Great Ormond Street Hospital, which allows senior trainees to step up to a consultant role.

Severe anemia contributes significantly to child mortality in sub-Saharan Africa. Blood transfusion is used in emergencies but carries risks. In BMC Medicine, Olupot-Olupot and colleagues report the findings of a phase II trial in children with severe anemia in Eastern Uganda. They provide important early safety and efficacy data supporting large volume whole blood transfusion (30 ml/kg) compared with the World Health Organization recommendation of 20 ml/kg. Large volume transfusions result in more rapid and frequent correction of severe anemia; they can be expected to reduce the risk of transfusions, and help manage the scarce resource of donor blood. However, severe anemia arises from varying combinations of acute, sub-acute and chronic etiologies. The Fluid Expansion As Supportive Therapy study reminds us that the risks and benefits of even simple interventions are complex, and that rapid normalization of physiology may not always be the best strategy. There is no substitute for high quality evidence and to this end we strongly support Olupot-Oluput and colleagues' call for a definitive trial of large volume transfusions in severe anemia. Please see related research article http://www.biomedcentral.com/1741-7015/12/67/abstract .