Heparin versus citrate anticoagulation for continuous renal replacement therapy in intensive care: the RRAM observational study.

BACKGROUND: In the UK, 10% of admissions to intensive care units receive continuous renal replacement therapy with regional citrate anticoagulation replacing systemic heparin anticoagulation over the last decade. Regional citrate anticoagulation is now used in > 50% of intensive care units, despite little evidence of safety or effectiveness. AIM: The aim of the Renal Replacement Anticoagulant Management study was to evaluate the clinical and health economic impacts of intensive care units moving from systemic heparin anticoagulation to regional citrate anticoagulation for continuous renal replacement therapy. DESIGN: This was an observational comparative effectiveness study. SETTING: The setting was NHS adult general intensive care units in England and Wales. PARTICIPANTS: Participants were adults receiving continuous renal replacement therapy in an intensive care unit participating in the Intensive Care National Audit & Research Centre Case Mix Programme national clinical audit between 1 April 2009 and 31 March 2017. INTERVENTIONS: Exposure - continuous renal replacement therapy in an intensive care unit after completion of transition to regional citrate anticoagulation. Comparator - continuous renal replacement therapy in an intensive care unit before starting transition to regional citrate anticoagulation or had not transitioned. OUTCOME MEASURES: Primary effectiveness - all-cause mortality at 90 days. Primary economic - incremental net monetary benefit at 1 year. Secondary outcomes - mortality at hospital discharge, 30 days and 1 year; days of renal, cardiovascular and advanced respiratory support in intensive care unit; length of stay in intensive care unit and hospital; bleeding and thromboembolic events; prevalence of end-stage renal disease at 1 year; and estimated lifetime incremental net monetary benefit. DATA SOURCES: Individual patient data from the Intensive Care National Audit & Research Centre Case Mix Programme were linked with the UK Renal Registry, Hospital Episode Statistics (for England), Patient Episodes Data for Wales and Civil Registrations (Deaths) data sets, and combined with identified periods of systemic heparin anticoagulation and regional citrate anticoagulation (survey of intensive care units). Staff time and consumables were obtained from micro-costing. Continuous renal replacement therapy system failures were estimated from the Post-Intensive Care Risk-adjusted Alerting and Monitoring data set. EuroQol-3 Dimensions, three-level version, health-related quality of life was obtained from the Intensive Care Outcomes Network study. RESULTS: Out of the 188 (94.9%) units that responded to the survey, 182 (96.8%) use continuous renal replacement therapy. After linkage, data were available from 69,001 patients across 181 intensive care units (60,416 during periods of systemic heparin anticoagulation use and 8585 during regional citrate anticoagulation use). The change to regional citrate anticoagulation was not associated with a step change in 90-day mortality (odds ratio 0.98, 95% confidence interval 0.89 to 1.08). Secondary outcomes showed step increases in days of renal support (difference in means 0.53 days, 95% confidence interval 0.28 to 0.79 days), advanced cardiovascular support (difference in means 0.23 days, 95% confidence interval 0.09 to 0.38 days) and advanced respiratory support (difference in means, 0.53 days, 95% CI 0.03 to 1.03 days) with a trend toward fewer bleeding episodes (odds ratio 0.90, 95% confidence interval 0.76 to 1.06) with transition to regional citrate anticoagulation. The micro-costing study indicated that regional citrate anticoagulation was more expensive and was associated with an estimated incremental net monetary loss (step change) of -£2376 (95% confidence interval -£3841 to -£911). The estimated likelihood of cost-effectiveness at 1 year was less than 0.1%. LIMITATIONS: Lack of patient-level treatment data means that the results represent average effects of changing to regional citrate anticoagulation in intensive care units. Administrative data are subject to variation in data quality over time, which may contribute to observed trends. CONCLUSIONS: The introduction of regional citrate anticoagulation has not improved outcomes for patients and is likely to have substantially increased costs. This study demonstrates the feasibility of evaluating effects of changes in practice using routinely collected data. FUTURE WORK: (1) Prioritise other changes in clinical practice for evaluation and (2) methodological research to understand potential implications of trends in data quality. TRIAL REGISTRATION: This trial is registered as ClinicalTrials.gov NCT03545750. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 13. See the NIHR Journals Library website for further project information

Can data fusion techniques predict adverse physiological events during haemodialysis?

Intra-dialytic haemodynamic instability is a common and disabling problem which may lead to morbidity and mortality though repeated organ ischaemia, but it has proven difficult to link any particular blood pressure threshold with hard patient outcomes. The relationship between blood pressure and downstream organ ischaemia during haemodialysis has not been well characterised. Previous attempts to predict and prevent intra-dialytic hypotension have had mixed results, partly due to patient and event heterogeneity. Using the brain as the indicator organ, we aimed to model the dynamic relationship between blood pressure, real-time symptoms, downstream organ ischaemia during haemodialysis, in order to identify the most physiologically grounded, prognostic definition of intra-dialytic decompensation. Following on from this, we aimed to predict the onset of intra-dialytic decompensation using personalised, probabilistic models of multivariate, continuous physiological data, ultimately working towards an early warning system for intra-dialytic adverse events. This was a prospective study of 60 prevalent haemodialysis patients who underwent extensive, continuous physiological monitoring of haemodynamic, cardiorespiratory, tissue oxygenation and dialysis machine parameters for 3-4 weeks. In addition, longitudinal cognitive function testing was performed at baseline and at 12 months. Despite their use in clinical practice, we found that blood pressure thresholds alone have a poor trade off between sensitivity and specificity for predicting downstream tissue ischaemia during haemodialysis. However, the performance of blood pressure thresholds could be improved by stratification for the presence or absence of cerebral autoregulation, and personalising thresholds according to the individual lower limit of autoregulation. For patients without autoregulation, the optimal blood pressure target was a mean arterial pressure (MAP) of 70mmHg. A key finding was that cumulative intra-dialytic exposure to cerebral ischaemia, but not to hypotension per se, corresponded to change in executive cognitive function over 12 months. Therefore we chose cerebral ischaemia as the definition of intra-dialytic decompensation for predictive modelling. We were able to demonstrate that the development of cerebral desaturation could be anticipated from earlier deviations of univariate physiological data from the expected trajectory for a given patient, but sensitivity was limited by the heterogeneity of events even within one individual. The most useful phys- iological data streams included peripheral saturation variance, cerebral saturation variance, heart rate and mean arterial pressure. Multivariate data fusion techniques using these variables created promising personalised models capable of giving an early warning of decompensation. Future work will involve the refinement and prospective testing of these models. In addition, we envisage a prospective study assessing the benefit of autoregulation-guided blood pressure targets on short term outcomes such as patient symptoms and wellbeing, as well as longer term outcomes such as cognitive function.</p