Systemic Heparin Anticoagulation Research Articles

Radiation Optic Neuropathy

Radiation optic neuropathy (RON) is a rapid-onset, severe, challanging optic neuropathy that can cause unilateral or bilateral vision loss, which may occur years after radiotherapy. RON mostly occurs with radiation therapy exceeding 50 Gy to the visual axis. The risk of RON occurring at radiation doses between 50-60 Gy is 5% within 10 years. Since RON can cause acute, irreversible, unilateral or bilateral profound vision loss, patients at risk need to be carefully monitored. Early diagnosis and treatment is very important to prevent serious vision loss. The first test to be performed in patients with suspected RON is fat-suppressed, non-contrast brain MRI, which is recommended to be performed in 3 mm and thinner sections. In addition; lumbar puncture and Optical coherence tomography angiography (OCT-A) are helpful tests in the differential diagnosis. Anti-VEGF molecules have been shown to be effective in treatment, which aim to reduce edema and retinal hemorrhages. Hyperbaric oxygen therapy is not a proven treatment for RON – but there are some studies about it’s speculated effect. Studies presenting the success rates of this treatment are quite limited in number. Systemic corticosteroids, heparin, warfarin and other anticoagulation treatments have not been proven successful in the treatment of RON. RON is one of the optic neuropathies that chronically damages visual function. The prognosis is generally poor. It is important for the patient and the physician to be aware of RON after radiotherapy and to minimize the possibility of permanent damage through preventive measures that can be taken. Since there are no definitive treatments for RON, preventive medicine is of great importance.

Citrate and low-dose heparin combined anticoagulation in pediatric continuous renal replacement therapy

There remains no optimal anticoagulation protocol for continuous renal replacement therapy (CRRT) with regional citrate anticoagulation (RCA) in pediatric patients with elevated D-dimer levels. We aimed to assess the effects of different anticoagulation strategies on the risk of CRRT filter clotting in these patients. Pediatric patients undergoing CRRT were retrospectively grouped based on pre-CRRT D-dimer levels and anticoagulant: D-RCA group (normal D-dimer, RCA only, n = 22), D+ RCA group (elevated D-dimer, RCA only, n = 50), and D+ RCA+ systemic heparin anticoagulation (SHA) group (elevated D-dimer, RCA combined with SHA, n = 55). The risk of filter clotting and incidence of bleeding were compared among the groups. Among the groups, the D+ RCA+ SHA group had the longest filter lifespan; further, the incidence of bleeding was not increased by concurrent use of low-dose heparin for anticoagulation. Moreover, concurrent heparin anticoagulation was associated with a decreased risk of filter clotting. Contrastingly, high pre-CRRT hemoglobin and D-dimer levels and post-filter ionized calcium level > 0.4 mmol/L were associated with an increased risk of filter clotting. RCA combined with low-dose heparin anticoagulation could reduce the risk of filter clotting and prolong filter lifespan without increasing the risk of bleeding in patients with elevated D-dimer levels undergoing CRRT.

Citrate anticoagulation and systemic heparin anticoagulation during continuous renal replacement therapy among critically-ill children

BakcgroundThe aim of this study was to evaluate the efficacy and safety of citrate versus heparin anticoagulation for CRRT in critically-ill children.MethodsThis retrospective comparative cohort reviewed the clinical records of critically-ill children undergoing CRRT with either RCA or systemic heparin anticoagulation. The primary outcome measure was hemofilter survival time. Secondary outcomes included the comparison of complications and metabolic disorders.ResultsA total of 131 patients (55 RCA and 76 systemic heparin) were included, in which a cumulative number of 280 hemofilters were used (115 in RCA with 5762 h total CRRT time, and 165 in systemic heparin with 6230 h total CRRT time). Hemofilter survival was significantly longer for RCA (51.0 h; IQR: 24–67 h) compared to systemic heparin (29.5 h; IQR, 17–48 h) (p = 0.002). Clotting-related hemofilter failure occurred in 9.6% of the RCA group compared to 19.6% in the systemic heparin group (p = 0.038). Citrate accumulation occurred in 4 (3.5%) of 115 RCA sessions. Hypocalcemia and metabolic alkalosis episodes were significantly more frequent in RCA recipients (35.7% vs 15.2%, p < 0.0001; 33.0% vs 19.4%, p = 0.009).ConclusionRCA is a safe and effective anticoagulation method for CRRT in critically-ill children and it prolongs hemofilter survival.ImpactRCA is superior to systemic heparin for the prolongation of circuit survival (overall and for clotting-related loss) during CRRT.These data indicate that RCA can be used to maximize the effective delivery of CRRT in critically-ill patients admitted to the PICU.There are potential cost-saving implications from our results owing to benefits such as less circuit downtime and fewer circuit changes.

Monocytes as Targets for Immunomodulation by Regional Citrate Anticoagulation.

Immune alterations in end-stage renal patients receiving hemodialysis are complex and predispose patients to infections. Anticoagulation may also play an immunomodulatory role in addition to the accumulation of uremic toxins and the effects of the dialysis procedure. Accordingly, it has been recently shown that the infection rate increases in patients under regional citrate anticoagulation (RCA) compared with systemic heparin anticoagulation (SHA). We hypothesized that RCA affects the immune status of hemodialysis patients by targeting monocytes. In a cohort of 38 end-stage renal patients undergoing hemodialysis, we demonstrated that whole blood monocytes of patients receiving RCA-but not SHA-failed to upregulate surface activation markers, like human leukocyte antigen class II (HLA-DR), after stressful insults, indicating a state of deactivation during and immediately after dialysis. Additionally, RNA sequencing (RNA-seq) data and gene set enrichment analysis of pre-dialysis monocytes evidenced a great and complex difference between the groups given that, in the RCA group, monocytes displayed a dramatic transcriptional change with increased expression of genes related to the cell cycle regulation, cellular metabolism, and cytokine signaling, compatible with the reprogramming of the immune response. Transcriptomic changes in pre-dialysis monocytes signalize the lasting nature of the RCA-related effects, suggesting that monocytes are affected even beyond the dialysis session. Furthermore, these findings demonstrate that RCA-but not SHA-impairs the response of monocytes to activation stimuli and alters the immune status of these patients with potential clinical implications.

Association of anticoagulation use during continuous kidney replacement therapy and 90-day outcomes: A multicentre study.

Anticoagulation is recommended during continuous kidney replacement therapy (CKRT) to prolong the filter lifespan for optimal filter performance. We aimed to evaluate the effect of anticoagulation during CKRT on dialysis dependence and mortality within 90 days of intensive care unit (ICU) admission. Our retrospective observational study evaluated the first CKRT session in critically ill adults with acute kidney injury (AKI) in Singapore from April to September 2017. The primary outcome was a composite of dialysis dependence or death within 90 days of ICU admission; the main exposure variable was anticoagulation use (regional citrate anticoagulation [RCA] or systemic heparin). Multivariable logistic regression was performed to adjust for possible confounders: age, female sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, liver dysfunction, coagulopathy (international normalised ratio[INR] >1.5) and platelet counts of less than 100,000/uL). The study cohort included 276 patients from 14 participating adult ICUs, of whom 176 (63.8%) experienced dialysis dependence or death within 90 days of ICU admission (19 dialysis dependence, 157 death). Anticoagulation significantly reduced the odds of the primary outcome (adjusted odds ratio [AOR] 0.47, 95% confidence interval [CI] 0.27-0.83, P=0.009). Logistic regression analysis using anticoagulation as a 3-level indicator variable demonstrated that RCA was associated with mortality reduction (AOR 0.46, 95% CI 0.25-0.83, P=0.011), with heparin having a consistent trend (AOR 0.51, 95% CI 0.23-1.14, P=0.102). Among critically ill patients with AKI, anticoagulation use during CKRT was associated with reduced dialysis or death at 90 days post-ICU admission, which was statistically significant for regional citrate anticoagulation and trended in the same direction of benefit for systemic heparin anticoagulation. Anticoagulation during CKRT should be considered whenever possible.

Evaluation of Proenkephalin A 119–159 for liberation from renal replacement therapy: an external, multicenter pilot study in critically ill patients with acute kidney injury

IntroductionRecent evidence suggests an association of plasma Proenkephalin A 119–159 (penKid) with early and successful liberation from continuous renal replacement therapy (CRRT) in critically ill patients with acute kidney injury. However, these exploratory results are derived from a monocentric trial and therefore require external validation in a multicenter cohort.MethodsData and plasma samples from the “Effect of Regional Citrate Anticoagulation versus Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury—A Randomized Clinical Trial” (RICH Trial) were used for this validation study. PenKid was measured in all plasma samples available at CRRT initiation and at day 3 of CRRT. Patients were categorized into low and high penKid groups with a cutoff at 100 pmol/l. Competing-risk time-to-event analyses were performed. Competing risk endpoints were successful and unsuccessful liberation from CRRT, the latter meaning death or initiation of a new RRT within one week of discontinuation of primary CRRT. Then penKid was compared to urinary output.ResultsLow pre-CRRT penKid levels at CRRT initiation were not associated with early and successful liberation from CRRT compared to patients with high pre-CRRT penKid levels [subdistribution hazard ratio (sHR) 1.01, 95% CI 0.73–1.40, p = 0.945]. However, the landmark analysis on day 3 of ongoing CRRT demonstrated an association between low penKid levels and successful liberation from CRRT (sHR 2.35, 95% CI 1.45–3.81, p < 0.001) and an association between high penKid levels and unsuccessful liberation (sHR 0.46, 95% CI 0.26–0.80, p = 0.007). High daily urinary output (> 436 ml/d) was even stronger associated with successful liberation (sHR 2.91, 95% CI 1.80–4.73, p < 0.001) compared to penKid.DiscussionThis study suggests that penKid may be a competent biomarker to monitor the recovery of kidney function during CRRT. This is in line with previous findings and investigated this concept in a multicenter cohort. Again, low penKid was associated with early and successful CRRT liberation, but was outperformed by high daily urinary output. The findings of this study now warrant further evaluation in prospective studies or a randomized controlled trial.Trial registration The RICH Trial was registered at clinicaltrials.gov: NCT02669589. Registered 01 February 2016.

P59: Treatment of Impella 5.5 Purge Dysfunction with Tissue Plasminogen Activator Prevents Subsequent Pump Exchanges

Background: The Impella 5.5 is a temporary, percutaneous left ventricular assist device (VAD) that contains a purge system to prevent blood from entering the motor housing. Acute pump failure can occur if purge flow is significantly disrupted and can be predicted by changes in purge pressure or flow rate. The use of alteplase (tPA) in a temporary purge solution is one intervention used to salvage pumps at risk of failure. We share our center’s experience using tPA to treat purge dysfunction in the Impella 5.5 population. Methods: We retrospectively reviewed all Impella 5.5 patients implanted at a single academic center from November 2020 to January 2023 (n=90). Cases were identified by tPA use in the purge system and purge dysfunction was verified by EMR documentation of a notable change in purge pressure or flow rate. Results: tPA was used to treat purge system dysfunction in 10 patients (11.1%) supported for an average of 25 days (Table 1). Nine patients (90%) had dextrose and sodium bicarbonate purge solution with systemic bivalirudin anticoagulation, and one patient had dextrose and heparin purge solution with systemic heparin anticoagulation. On average, purge dysfunction requiring tPA use occurred on post-operative day 13 and required 10 ± 9 mg of tPA in solution. Nine patients (90%) had successful restoration of baseline purge pressure and flow following tPA administration, while the other patient was transitioned to comfort measures shortly after and success could not be determined. No patients required a pump exchange for continued purge dysfunction. Of those treated with tPA, 6 patients (55%) survived to discharge. Other than an incidental finding in one patient questionable for subarachnoid hemorrhage that not impacting clinical care, there were no other major bleeding events or strokes within 48 hours of tPA administration. Conclusion: In cases of identified purge dysfunction prior to pump failure, tPA is an effective intervention for resolution and return to baseline purge function in the Impella 5.5 device preventing the need for surgical pump exchange.

Regional citrate anticoagulation versus systemic heparin anticoagulation for continuous kidney replacement therapy in intensive care

PurposeMany intensive care units (ICUs) have transitioned from systemic heparin anticoagulation (SHA) to regional citrate anticoagulation (RCA) for continuous kidney replacement therapy (CKRT). We evaluated the clinical and health economic impacts of ICU transition to RCA. Materials and methodsWe surveyed all adult general ICUs in England and Wales to identify transition dates and conducted a micro-costing study in eight ICUs. We then conducted an interrupted time-series analysis of linked, routinely collected health records. ResultsIn 69,001 patients who received CKRT (8585 RCA, 60,416 SHA) in 181 ICUs between 2009 and 2017, transition to RCA was not associated with a change in 90-day mortality (adjusted odds ratio 0.98, 95% CI 0.89–1.08) but was associated with step-increases in duration of kidney support (0.53 days, 95% CI 0.28–0.79), advanced cardiovascular support (0.23 days, 95% CI 0.09–0.38) and ICU length of stay (0.86 days, 95% CI 0.24–1.49). The estimated one-year incremental net monetary benefit per patient was £ − 2376 (95% CI £ − 3841–£ − 911), with an estimated likelihood of cost-effectiveness of <0.1%. ConclusionsTransition to RCA was associated with significant increases in healthcare resource use, without corresponding clinical benefit, and is highly unlikely to be cost-effective over a one-year time horizon.

Regional citrate anticoagulation vs systemic heparin anticoagulation for double-filtration plasmapheresis.

Double-filtration plasmapheresis (DFPP) has been utilized for immunomodulation in kidney transplantation. Anticoagulation is important to maintain circuit patency during DFPP. We aimed to compare the efficacy and safety of regional citrate anticoagulation (RCA) with systemic heparin anticoagulation during DFPP in kidney transplant recipients. A retrospective cohort study was conducted to compare the efficacy and safety of RCA (RCA-DFPP) to systemic heparin anticoagulation (Hep-DFPP) for DFPP among kidney transplant recipients in a single tertiary center. A total of 112 sessions of DFPP were performed for 23 subjects, of which 62 sessions were RCA-DFPP and 50 sessions were Hep-DFPP. There were 13 sessions (11.6%) of premature circuit clotting, 10 sessions (16.1%) for RCA-DFPP and 3 sessions (6.0%) for Hep-DFPP (P=.10). All premature circuit clotting episodes occurred in subjects who underwent DFPP through a vascular catheter. Premature circuit clotting was associated with the use of a vascular catheter (odds ratio [OR] 14.2, 95% confidence interval [CI] 2.7-73.7; P < .01) and high postfilter ionized calcium (OR 12.7, 95% CI 1.4-112.5; P < .01). There was no major bleeding event. Hep-DFPP was associated with higher occurrence of hypocalcemia (OR 1.1, 95% CI 1.0-1.2; P < .01) and metabolic acidosis (OR 1.4, 95% CI 1.2-2.0; P=.04), while hypomagnesemia was more common for RCA-DFPP (OR 2.9, 95% CI 1.1-7.4; P=.03). Amongst kidney transplant patients who receive DFPP therapy, RCA-DFPP may be comparable to Hep-DFPP for the maintenance of circuit patency. Functioning vascular access is vital in avoiding premature clotting of the circuit. Close monitoring of electrolyte imbalances and coagulopathy related to DFPP is recommended.

Analysis of Leukocyte Recruitment in Continuous Veno-Venous Hemofiltration with Regional Citrate vs. Systemic Heparin Anticoagulation.

Acute kidney injury (AKI) is a frequent complication in critically ill patients. Supportive treatment of AKI patients is based on renal-replacement therapy, including continuous veno-venous hemofiltration (CVVH). To limit clotting events on extracorporeal surfaces, anticoagulants are administered, including systemic heparin and local citrate. The differential and comparative effects of these anticoagulants on leukocyte function in acute kidney injury patients are, so far, insufficiently understood. In this bio-add-on-study, AKI patients were randomized as part of a parallel-group trial to either systemic heparin or regional citrate anticoagulation. Patient samples were collected upon inclusion, prior to CVVH initiation at day 0, day 1, day 3 and day 5, following CVVH initiation, and one day after cessation of CVVH, then immediately analyzed. Flow cytometric assessment of surface-receptor molecules was conducted. Whole-blood-perfused human microfluidic chambers were used for the analysis of neutrophil rolling and adhesion. Acute kidney injury was associated with significant changes in the surface expression of CD182 and CD16 throughout CVVH treatment, independent of the anticoagulation regime. AKI furthermore abrogated selectin-induced slow leukocyte rolling and diminished chemokine-induced leukocyte arrest. Subgroup analyses of citrate vs. heparin treatment showed no significant differences between groups, independent of the duration of CVVH treatment. CD182 and CD16 expression remained low in both groups throughout CVVH therapy. These data confirm that AKI impairs selectin-mediated leukocyte slow rolling and chemokine-induced leukocyte arrest in vitro. Systemic heparin or local citrate anticoagulation have no differential effect on the leukocyte recruitment steps examined in this study.

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

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. 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. This was an observational comparative effectiveness study. The setting was NHS adult general intensive care units in England and Wales. 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. 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. 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. 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. 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%. 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. 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. (1) Prioritise other changes in clinical practice for evaluation and (2) methodological research to understand potential implications of trends in data quality. This trial is registered as ClinicalTrials.gov NCT03545750. 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.

Anticoagulation polyvinyl chloride extracorporeal circulation catheters for heparin-free treatment.

Extracorporeal circulation (ECC) catheters have potential to be blood compatible and could be used to prevent thrombotic occlusion. Here, we produced heparin-mimicking anticoagulation PVC tubing on a large scale by synthesizing a heparin-mimicking polymer (HMP) and co-extruding. The PVC@HMP catheter was evaluated using whole human blood in vitro, which indicated it could prevent plasma protein attachment, reduce platelet adhesion and activation, and inhibit coagulation factors (XII, XI, IX, and VIII). Moreover, the anticoagulation PVC tubing was assembled into extracorporeal circulation with a New Zealand rabbit model, manifesting excellent real-time antithrombogenic properties without systemic heparin anticoagulation in vivo. The rapid recovery of coagulation factors after operation further confirmed its superiority over heparin, which would not completely inactivate the activity of those coagulation factors (XII, XI, IX and VIII). In addition, the PVC@HMP-1 catheters remain patent after being implanted in rats for 28 days without apparent inflammation and mortality complications. The anticoagulation PVC tubes could be used to construct various systemic and integrative anticlotting biomedical devices, which would dramatically reduce the introduction of heparin into blood circulation, thus preventing side effects and promoting the development of heparin-free treatment.

Early Initiation of Extracorporeal Blood Purification Using the AN69ST (oXiris®) Hemofilter as a Treatment Modality for COVID-19 Patients: a Single-Centre Case Series.

IntroductionSevere coronavirus disease 2019 (COVID-19) is characterised by hyperinflammatory state, systemic coagulopathies, and multiorgan involvement, especially acute respiratory distress syndrome (ARDS). We here describe our preliminary clinical experience with COVID-19 patients treated via an early initiation of extracorporeal blood purification combined with systemic heparinisation and respiratory support.MethodsFifteen patients were included; several biomarkers associated with COVID-19 severity were monitored. Personalised treatment was tailored according to the levels of interleukin (IL)-6, IL-8, tumour necrosis factor alpha, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio, thrombocyte counts, D-dimers, and fibrinogen. Treatment consisted of respiratory support, extracorporeal blood purification using the AN69ST (oXiris®) hemofilter, and 300 U/kg heparin to maintain activation clotting time ≥ 180 seconds.ResultsTen patients presented with severe to critical disease (dyspnoea, hypoxia, respiratory rate > 30/min, peripheral oxygen saturation < 90%, or > 50% lung involvement on X-ray imaging). The median intensive care unit length of stay was 9.3 days (interquartile range 5.3-10.1); two patients developed ARDS and died after 5 and 26 days. Clinical improvement was associated with normalisation (increase) of thrombocytes and white blood cells, stable levels of IL-6 (< 50 ng/mL), and a decrease of CRP and fibrinogen.ConclusionContinuous monitoring of COVID-19 severity biomarkers and radiological imaging is crucial to assess disease progression, uncontrolled inflammation, and to avert irreversible multiorgan failure. The combination of systemic heparin anticoagulation regimens and extracorporeal blood purification using cytokine-adsorbing hemofilters may reduce hyperinflammation, prevent coagulopathy, and support clinical recovery.

Effect of Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury

Although current guidelines suggest the use of regional citrate anticoagulation (which involves the addition of a citrate solution to the blood before the filter of the extracorporeal dialysis circuit) as first-line treatment for continuous kidney replacement therapy in critically ill patients, the evidence for this recommendation is based on few clinical trials and meta-analyses. To determine the effect of regional citrate anticoagulation, compared with systemic heparin anticoagulation, on filter life span and mortality. A parallel-group, randomized multicenter clinical trial in 26 centers across Germany was conducted between March 2016 and December 2018 (final date of follow-up, January 21, 2020). The trial was terminated early after 596 critically ill patients with severe acute kidney injury or clinical indications for initiation of kidney replacement therapy had been enrolled. Patients were randomized to receive either regional citrate anticoagulation (n = 300), which consisted of a target ionized calcium level of 1.0 to 1.40 mg/dL, or systemic heparin anticoagulation (n = 296), which consisted of a target activated partial thromboplastin time of 45 to 60 seconds, for continuous kidney replacement therapy. Coprimary outcomes were filter life span and 90-day mortality. Secondary end points included bleeding complications and new infections. Among 638 patients randomized, 596 (93.4%) (mean age, 67.5 years; 183 [30.7%] women) completed the trial. In the regional citrate group vs systemic heparin group, median filter life span was 47 hours (interquartile range [IQR], 19-70 hours) vs 26 hours (IQR, 12-51 hours) (difference, 15 hours [95% CI, 11 to 20 hours]; P < .001). Ninety-day all-cause mortality occurred in 150 of 300 patients vs 156 of 296 patients (Kaplan-Meier estimator percentages, 51.2% vs 53.6%; unadjusted difference, -2.4% [95% CI, -10.5% to 5.8%]; unadjusted hazard ratio, 0.91 [95% CI, 0.72 to 1.13]; unadjusted P = .38; adjusted difference, -6.1% [95% CI, -12.6% to 0.4%]; primary adjusted hazard ratio, 0.79 [95% CI, 0.63 to 1.004]; primary adjusted P = .054). Of 38 prespecified secondary end points, 34 showed no significant difference. Compared with the systemic heparin group, the regional citrate group had significantly fewer bleeding complications (15/300 [5.1%] vs 49/296 [16.9%]; difference, -11.8% [95% CI, -16.8% to -6.8%]; P < .001) and significantly more new infections (204/300 [68.0%] vs 164/296 [55.4%]; difference, 12.6% [95% CI, 4.9% to 20.3%]; P = .002). Among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy, anticoagulation with regional citrate, compared with systemic heparin anticoagulation, resulted in significantly longer filter life span. The trial was terminated early and was therefore underpowered to reach conclusions about the effect of anticoagulation strategy on mortality. ClinicalTrials.gov Identifier: NCT02669589.

P0625CONTINUOUS RENAL REPLACEMENT THERAPY WITHOUT ANTICOAGULATION IN CRITICALLY ILL PATIENTS AT HIGH RISK OF BLEEDING-A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background and Aims Continuous renal replacement therapy (CRRT) has been widely used in the critical care setting and anticoagulation is usually necessitated. However, critically ill patients are commonly at incremental risk of bleeding, which contributed to the hesitation of anticoagulant use for CRRT in clinical practice. The current guideline recommended CRRT proceed without anticoagulation in patients with contraindication to citrate and increased bleeding risk. Nevertheless, the efficacy of anticoagulation-free CRRT remains inconsistent. Therefore, the purpose of our present systematic review is to evaluate the efficacy and safety of anticoagulant-free CRRT based on the current literatures. Method We conducted a comprehensive search of PubMed (US National Library of Medicine, Bethesda, MD, USA), Cochrane Library databases and EMBASE from database inception to January 12, 2019 for potential candidate studies. Studies included adult critically ill (age &amp;gt; 18 years) patients with increased bleeding risk, and underwent CRRT without anticoagulation were considered for the inclusion. Results Finally, 17 observational studies and 3 randomized controlled trials with 1615 patients were included in our present meta-analysis. There was no significant difference in filter lifespan between the anticoagulation-free and systemic heparin group. The filter lifespan was significantly prolonged in the citrate (WMD -23.01, 95%CI [-28.62, -17.39], P &amp;lt; 0.001; I2 = 0%, P = 0.53) and nafamostat (WMD -8.4, 95%CI [-9.9, -6.9], P &amp;lt; 0.001; I2 = 33.7%, P = 0.21) groups, compared with anticoagulation-free group. The averaged filter lifespan of the anticoagulation-free CRRT ranged from 10.2 to 52.5 hours. Conclusion The filter lifespan in anticoagulation-free patients with increased bleeding risk was comparable to that in patients without increased bleeding risk underwent systemic heparin anticoagulation CRRT. Nafamostat was not recommended for CRRT anticoagulation due to its drawbacks. Currently, the optimal choice of anticoagulation strategy for critically ill patients without citrate contraindications at high risk of bleeding should be regional citrate anticoagulation. Further studies should focus on the special cut-off value of activated partial thromboplastin time (APTT), international normalized ratio (INR) and platelet (PLT) count, at which the anticoagulation-free CRRT would be beneficial.

Renal replacement anticoagulant management: Protocol and analysis plan for an observational comparative effectiveness study of linked data sources.

Acute kidney injury is common in critical illness. In patients with severe acute kidney injury, renal replacement therapy is needed to prevent harm from metabolic and electrolyte disturbances and fluid overload. In the UK, continuous renal replacement therapy (CRRT) is the preferred modality, which requires anticoagulation. Over the last decade, conventional systemic heparin anticoagulation has started being replaced by regional citrate anticoagulation for CRRT, which is now used in approximately 50% of ICUs. This shift towards regional citrate anticoagulation for CRRT is occurring with little evidence of safety or longer term effectiveness. Renal replacement anticoagulant management (RRAM) is an observational comparative effectiveness study, utilising existing data sources to address the clinical and cost-effectiveness of the change to regional citrate anticoagulation for CRRT in UK ICUs. The study will use data from approximately 85,000 patients who were treated in adult, general ICUs participating in the case mix programme national clinical audit between 1 April 2009 and 31 March 2017. A survey of health service providers' anticoagulation practices will be combined with treatment and hospital outcome data from the case mix programme and linked with long-term outcomes from the Civil Registrations (deaths), Hospital Episodes Statistics for England, Patient Episodes Data for Wales, and the UK Renal Registry datasets. The primary clinical effectiveness outcome is all-cause mortality at 90-days. The study will incorporate an economic evaluation with micro-costing of both regional citrate anticoagulation and systemic heparin anticoagulation. Study registration: NCT03545750.

Hemodialysis Does Not Induce Detectable Activation of the Contact System of Coagulation

IntroductionSystemic anticoagulation is administered during hemodialysis to prevent clotting of the extracorporeal circuit. The role of contact system activation in thrombin generation during hemodialysis using current era dialyzer membranes is unknown.MethodsWe performed a single-center randomized crossover study. Ten patients treated with hemodialysis underwent 3 standardized hemodialysis sessions. For every patient, each session was performed with a different type of dialyzer membrane (polyphenylene [PP], polymethylmetacrylate [PMMA], polyethylenimine-coated polyacrylonitrile [AN69ST]). Blood samples were collected before and 5, 15, 30, 90, and 240 minutes after blood pump start to evaluate coagulation activation (thrombin–antithrombin complex [TAT], prothrombin fragment 1+2 [PF1+2], activated factor XII [FXIIa], kallikrein, activated factor XI [FXIa]). Plasma of healthy volunteers (n = 20) was used as a reference.ResultsBaseline TAT and PF1+2 levels were higher in hemodialysis patients compared to healthy controls (median [interquartile range] for TAT: 3.3 [2.9–4.2] vs. 2.4 [2.3–2.5] μg/l [P = 0.0002] and for PF1+2: 647 [478–737] vs. 138 [125–254] pmol/l [P < 0.0002]). Despite the use of systemic anticoagulation, TAT further increased during treatment, with the increase starting after 30 minutes (median TAT at t240: 9.0 μg/l (PP), 5.5 μg/l (PMMA), and 7.2 μg/l (AN69ST), all P < 0.05 vs. baseline). Contact system markers FXIIa and kallikrein did not differ significantly between dialysis patients and healthy controls, whereas baseline FXIa levels were significantly lower in dialysis patients compared to healthy controls (P = 0.001). Levels of all contact system markers remained unchanged during hemodialysis with all types of dialyzer membranes.ConclusionRoutine hemodialysis using systemic heparin anticoagulation induces coagulation activation without measurable contact system activation.

Continuous Renal Replacement Therapy in Venovenous Extracorporeal Membrane Oxygenation: A Retrospective Study on Regional Citrate Anticoagulation.

Systemic infusion of unfractionated heparin (UFH) is the standard anticoagulation technique for continuous renal replacement therapy (CRRT) during extracorporeal membrane oxygenation (ECMO), but often fails to avoid CRRT circuit clotting. The aim of this study was to assess, in patients undergoing CRRT during venovenous ECMO (vv-ECMO), the efficacy and safety of adding regional citrate anticoagulation (RCA) for CRRT circuit anticoagulation (RCA + UFH group) compared with the sole systemic heparin anticoagulation (UFH group). We performed a retrospective chart review (2009-2018) of patients treated with CRRT during ECMO. We evaluated filter life span, rate of CRRT circuit clotting, and coagulation parameters. The incidence of citrate anticoagulation-related complications was recorded. Forty-eight consecutive adult patients underwent CRRT during vv-ECMO in the study period. The incidence of CRRT circuit clotting was lower in the RCA + UFH group (11% vs. 38% in the UFH group, p < 0.001). Log-rank survival analysis demonstrated longer circuit lifetime for RCA + UFH group. No complication ascribable to citrate anticoagulation was recorded. Regional citrate anticoagulation resulted a feasible, safe, and effective technique as additional anticoagulation for CRRT circuits during ECMO. Compared with systemic heparinization only, this technique allowed to reduce the rate of CRRT circuit clotting.

Regional citrate versus systemic heparin anticoagulation for continuous renal replacement therapy in critically ill children.

Anticoagulation is used to prevent filter clotting in patients undergoing continuous renal replacement therapy. Regional citrate anticoagulation is associated with lower rates of bleeding complications and prolongs the filter life span; however, a number of metabolic side effects had been associated with this therapy. The aim of this study was to evaluate the effect and safety of citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill children. A retrospective comparative cohort study. Department of Pediatric Intensive Care, Acibadem Mehmet Ali Aydınlar University School of Medicine. From August 2016 to August 2018, 45 patients (19 in the citrate group and 26 in the heparin group) were included. A total of 101 hemofilters were used in all therapies: 44 in the citrate group (total continuous renal replacement therapy time: 2699 h) and 57 in the heparin group (total continuous renal replacement therapy time: 2383 h). The median circuit lifetime was significantly longer for regional citrate anticoagulation (53.0; interquartile range, 40-70 h) than for heparin anticoagulation (40.25; interquartile range, 22.75-53.5 h; p = 0.025). Mortality rates were similar in both groups (31.58% vs 30.77%). The most common indication for dialysis was hypervolemia in both groups. Transfusion rates were 1.65 units (interquartile range, 0.5-2.38) with heparin and 0.8 units (interquartile range, 0.3-2.0) with citrate (p = 0.32). Clotting-related hemofilter failure occurred in 11.36% of filters in the citrate group compared with 26.31% of filters in the heparin group. Our study showed that citrate is superior in terms of safety and efficacy, with longer filter life span. Regional citrate should be considered as a better anticoagulation method than heparin for continuous renal replacement therapy in critically ill children.

Intrasinus Thrombolysis for Cerebral Venous Sinus Thrombosis: Single-Center Experience.

Objective: The purpose of this research was to study the safety and efficacy of intrasinus thrombolysis in patients with cerebral venous sinus thrombosis unresponsive to conventional heparin therapy.Methods: A total of 156 CVST patients were treated using interventional thrombolysis in our center from January 2010 to June 2018. Clinical data, including duration of symptoms, indications and outcome of IST were retrieved, and outcomes were analyzed. DSA or MRV was used to assess the recanalization after thrombolysis. mRS was used to evaluate the outcome at admission, discharge, and follow-up.Results: 91.38% of patients obtained functional independence (mRS 0–2). The mRS score was 0–2 in 120 patients (76.92%, 120/156) at the time of discharge. Seven patients succumbed during hospitalization. MRV examination was performed in 149 patients, and the results showed that the venous sinus of 112 patients (75.17%) was completely recanalized, and it was partially recanalized in 28 patients (18.79%) and nine patients (6.04%) had no recanalization at the time of discharge. In total, 116 patients were followed up at least for 6 months, 89 patients (76.72%) were completely recanalized, 21 patients (18.1%) were partially recanalized, and six patients (5.17%) were not recanalized.Conclusion: IST may be more effective than systemic heparin anticoagulation in moribund and unresponsive patients despite the risk of hemorrhage. Large randomized controlled trials are required to further evaluate this issue.