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Background Coronavirus disease 2019 (COVID-19) may predispose patients to thrombotic events. The best anticoagulation strategy for continuous renal replacement therapy (CRRT) in such patients is still under debate. The purpose of this study was to evaluate the impact that different anticoagulation protocols have on filter clotting risk. Methods This was a retrospective observational study comparing two different anticoagulation strategies (citrate only and citrate plus intravenous infusion of unfractionated heparin) in patients with acute kidney injury (AKI), associated or not with COVID-19 (COV + AKI and COV − AKI, respectively), who were submitted to CRRT. Filter clotting risks were compared among groups. Results Between January 2019 and July 2020, 238 patients were evaluated: 188 in the COV + AKI group and 50 in the COV − AKI group. Filter clotting during the first filter use occurred in 111 patients (46.6%). Heparin use conferred protection against filter clotting (HR = 0.37, 95% CI 0.25–0.55), resulting in longer filter survival. Bleeding events and the need for blood transfusion were similar between the citrate only and citrate plus unfractionated heparin strategies. In-hospital mortality was higher among the COV + AKI patients than among the COV − AKI patients, although it was similar between the COV + AKI patients who received heparin and those who did not. Filter clotting was more common in patients with D-dimer levels above the median (5990 ng/ml). In the multivariate analysis, heparin was associated with a lower risk of filter clotting (HR = 0.28, 95% CI 0.18–0.43), whereas an elevated D-dimer level and high hemoglobin were found to be risk factors for circuit clotting. A diagnosis of COVID-19 was marginally associated with an increased risk of circuit clotting (HR = 2.15, 95% CI 0.99–4.68). Conclusions In COV + AKI patients, adding systemic heparin to standard regional citrate anticoagulation may prolong CRRT filter patency by reducing clotting risk with a low risk of complications.

IntroductionThe only supportive therapy for patients with severe acute kidney injury (AKI), a common complication among the critically ill, is dialysis. Based on the literature and current guidelines, continuous renal replacement therapy (CRRT) with a total effluent dose of 20–25 mL/kg/hour and adjustments to ensure such dose is delivered despite down time (eg, due to surgical procedures) is recommended. However, experimental and clinical studies suggest that azotaemia, which can be induced by lowering the effluent dose, may accelerate renal recovery. This clinical study investigates whether a lower effluent dose (10–15 mL/kg/hour) for a maximum of 7 days or until successful (>24 hours) liberation of CRRT in critically ill patients with a dialysis-dependent AKI accelerates renal recovery and reduces time on CRRT compared with guideline-directed standard dose (25–30 mL/kg/hour).Methods and analysisThe Ketzerei trial is an international, multicentre randomised, controlled trial, designed to investigate if a lower effluent dose (10–15 mL/kg/hour) accelerates renal recovery and reduces the time on CRRT compared with the guideline directed standard effluent dose (25–30 mL/kg/hour). The study aims to enrol 150 critically ill patients with a dialysis-dependent AKI. Eligible patients will be randomised to receive either a standard effluent dose (control group, 25–30 mL/kg/hour) or lower effluent dose (interventional group, 10–15 mL/kg/hour). The primary endpoint is the number of days free from CRRT and alive (from randomisation through day 28). Key secondary endpoints include the number of (serious) adverse events due to potential uremia, the duration of RRT and intensive care unit survival.Ethics and disseminationThe Ketzerei trial has been approved by the Ethics Committee of the Chamber of Physicians Westfalen-Lippe (2023–343 f-s), the University of Muenster and subsequently by the corresponding Ethics Committee of the participating sites. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration numberclinicaltrials.gov (NCT06021288).

Objectives The primary objective is to test if heparin added to a standard regional anticoagulation protocol based on citrate is able to reduce dialysis circuit losses by clotting without increasing the risk of thrombocytopenia or bleeding, in patients with COVID-19 with acute kidney injury requiring dialysis. Trial design Randomized, parallel-group, open-label trial, with two arms (ratio 1:1) comparing different continuous renal replacement therapy anticoagulation strategies. Participants Eligibility conditions: All ICU patients of University of Sao Paulo General Hospital (Hospital das Clínicas), Brazil will be screened for eligibility conditions. Adults (> 18 years old) with confirmed COVID-19 and acute kidney injury requiring dialysis with agreement between ICU and nephrology teams for the introduction of renal continuous replacement therapy in daily ICU rounds. Continuous renal replacement therapy will be prescribed by consulting nephrologists based on standard clinical guidelines, including acute kidney injury with hemodynamic instability plus hyperkalemia, severe acidosis, volume overload, respiratory distress, multiorgan failure or some combination of these factors. Data Collection: Patients demographics and associated clinical data and comorbidities will be recorded at ICU entry. Demographic information will include the patient’s age, sex, and admission dates. Clinical data comprise comorbidities, APACHE 2, SAPS 3, need for mechanical ventilation, and use of vasopressor drugs. Physiological data collected by the day of CRRT start will be vital signs, the arterial oxygen tension/fraction of inspired oxygen (PaO2/FiO2) index, and serum creatinine, blood urea nitrogen, bilirubin, hemoglobin, hematocrit, platelets, white blood cell count levels and Peak D-dimer levels. Patients will be analyzed for the first 72h of CRRT, and they will be evaluated regarding clinical variables, filter patency and any adverse events that could be related to the anticoagulation choice, as bleeding (mild or major) or low platelets counts (<100.000 ui/uL) during treatment period. Mild and major bleeding will be defined by hemorrhagic event without clinical impact or hemoglobin (Hb) fall lesser than 1g/dL and hemorrhagic event with clinical impact or Hb fall higher than 1g/dL, respectively. Exclusion criteria: Hypersensitivity to any of the substances going to be used in the study (Citric acid dextrosol 2.2% and unfractionated heparin); Previous diagnosis of coagulopathy or thrombophilia; Contraindication to the use of unfractionated heparin; Risk of citrate poisoning - (Lactate> 30 mg/dL, international normalized ratio > 2.5, Total bilirubin> 15 mg/dL); Pregnancy; Patients unlikely to survive for more than 24 hours. The trial is being undertaken at the University of Sao Paulo General Hospital (Hospital das Clinicas), Brazil. Intervention and comparator Group A (control) - Patients on continuous renal replacement therapy (blood flow 150 ml/min, dose of 30 mL/Kg/h) receiving anticoagulation with sodium citrate at 4 mmol/L Group B (experiment): Patients on continuous hemodialysis (blood flow 150 mL/min, dose of 30 mL/Kg/h) receiving anticoagulation with sodium citrate at 4 mmol/L associated with unfractionated heparin at 10 U/Kg/h. Main outcomes The percentage of clotted dialyzers within 72 hours in each of the studied groups (Primary outcome) Secondary outcomes: Number of dialyzers used in the first 72 hours of dialysis protocol, Mortality in the first 72 h of dialysis protocol, Bleeding events (Major or minor) in the first 72 h of dialysis protocol, Thrombocytopenia (less than 50.000 platelets) proportion in the first 72 h of dialysis protocol, Dialysis efficiency (Urea sieving) - variation in urea sieving between the first, second and third days of dialysis protocol, Continuous renal replacement therapy pressures (Arterial, Venous, dialysate and pre-filter pressure) in the first 72 h of dialysis protocol, in-hospital mortality. Randomization RedCap→ randomization – 2 blocks randomization by D-dimer level (5000ng/dL cut-off) and catheter site (Right Internal Jugular versus other sites) with 1:1 allocation ratio. Blinding (masking) No blinding – Open label format Numbers to be randomized (sample size) Total number of patients 90 (45 per group) Trial Status Trial version 2.0 – ongoing recruitment. First recruitment: June 29, 2020 Estimated date for last recruitment: December 31, 2020 Trial registration Responsible Party: University of Sao Paulo General Hospital (Hospital das Clinicas) ClinicalTrials.gov Identifier: NCT04487990 , registered July 27, 2020, ReBec www.ensaiosclinicos.gov.br/rg/RBR-45kf9p/ Other Study ID Numbers: U1111-1252-0194 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ) In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

The objective of this study was to determine the impact of the timing of KRT, dichotomized by a temporal criterion or by creatinine level, in patients with COVID-19–related AKI. This was a retrospective study involving 512 adult patients admitted to the ICU. All participants had laboratory-confirmed COVID-19 and a confirmed diagnosis of AKI. The potential predictors were the determination of the timing of KRT based on a temporal criterion (days since hospital admission) and that based on a serum creatinine cutoff criterion. Covariates included age, sex, and the SOFA score, as well as the need for mechanical ventilation and vasopressors. The main outcome measure was in-hospital mortality. We evaluated 512 patients, of whom 69.1% were men. The median age was 64 years. Of the 512 patients, 76.6% required dialysis after admission. The overall in-hospital mortality rate was 72.5%. When the timing of KRT was determined by the temporal criterion, the risk of in-hospital mortality was significantly higher for later KRT than for earlier KRT—84% higher in the univariate analysis (OR = 1.84, 95%, [CI]: 1.10–3.09) and 140% higher after adjustment for age, sex, and SOFA score (OR = 2.40, 95% CI: 1.36–4.24). When it was determined by the creatinine cutoff criterion, there was no such difference between high and low creatinine at KRT initiation. In patients with COVID-19–related AKI, earlier KRT might be associated with lower in-hospital mortality.

Demographic, clinical, and serum biochemical characteristics of patients admitted to the intensive care unit with severe coronavirus disease 2019a and treated with glucocorticoids Patient Age Sex SAPS 2 Crb Ureab Minimum Na Maximum K Pre-treatment Post-treatment DHEA Cortisol Ald Average K Average Na Urea (years) (mg/dL) (mg/dL) (mEq/L) (mEq/L) (ng/mL) (µg/dL) (ng/dL) (mEq/L) (mEq/L) (mg/dL) 1 70 M 88 13.48 332 134 7.4 ND ND ND 3.4 155 98 2 69 M 89 11.12 228 133 7.0 ND ND ND 3.9 146 50 3 65 M 71 10.52 145 127 7.9 ND 25.8 21.4 3.4 136 38 4 60 F 82 6.5 298 130 7.3 ND ND ND 4.1 138 100 5 65 M 80 4.63 99 127 7.5 ND ND ND 3.5 143 83 6 73 M 75 5.16 131 131 6.0 151 28.4 7.9 3.3 150 48 7 68 M 80 3.29 229 133 7.8 ND ND ND 3.7 145 86 8 76 M 49 0.92 314 132 6.8 ND ND ND 3 145 48 9 59 M 82 10.92 158 130 7.6 365 33 40.5 4 147 92 10 66 F ND 3.2 134 128 6.7 93 12.1 15.5 3.6 141 67 11 73 M 93 1.88 113 132 6.3 ND ND 7.8 3.9 144 88 12 76 F 79 0.8 26 126 7.3 ND 30.5 41.5 3.3 148 20 13 78 M 59 2.5 78 130 7.1 ND 14.8 ND 4.2 140 30 SAPS 2 Simplified Acute Physiology Score 2, Cr creatinine, DHEA dehydroepiandrosterone, Ald aldosterone, ND no data aAll of the patients tested positive for infection with severe acute respiratory syndrome coronavirus 2, on high-throughput sequencing real-time reverse transcriptase–polymerase chain reaction assay of nasal-pharyngeal/tracheal swab specimens or on an antibody test bAt admission Cortisol deficiency can be difficult to diagnose in ICU patients because the clinical indicators are frequently nonspecific [3]. In one recent systematic review [6], the authors summarized data on the occurrence of adrenal insufficiency in patients with COVID-19. In another autopsy study evaluating adrenal vascular changes in patients who died from COVID-19 [8], the authors demonstrated acute fibrinoid necrosis of small vessels, mainly arterioles, in the adrenal parenchyma, adrenal capsule, and immediately adjacent periadrenal adipose tissue. The study was approved by the Institutional Ethics Board of the University of São Paulo School of Medicine Hospital das Clínicas (Reference no. 4.129.320).