Cytokine hemoadsorption with CytoSorb® in post-cardiac arrest syndrome, a pilot randomized controlled trial.

BACKGROUND: Hemoadsorption (HA) might mitigate the systemic inflammatory response associated with post-cardiac arrest syndrome (PCAS) and improve outcomes. Here, we investigated the feasibility, safety and efficacy of HA with CytoSorb® in cardiac arrest (CA) survivors at risk of PCAS. METHODS: In this pilot randomized controlled trial, we included patients admitted to our intensive care unit following CA and likely to develop PCAS: required norepinephrine (> 0.2 µg/kg/min), and/or had serum lactate > 6 mmol/l and/or a time-to-return of spontaneous circulation (ROSC) > 25 min. Those requiring ECMO or renal replacement therapy were excluded. Eligible patients were randomly allocated to either receive standard of care (SOC) or SOC plus HA. Hemoadsorption was performed as stand-alone therapy for 24 h, using CytoSorb® and regional heparin-protamine anticoagulation. We collected feasibility, safety and clinical data as well as serial plasma cytokines levels within 72 h of randomization. RESULTS: We enrolled 21 patients, of whom 16 (76%) had out-of-hospital CA. Median (IQR) time-to-ROSC was 30 (20, 45) minutes. Ten were assigned to the HA group and 11 to the SOC group. Hemoadsorption was initiated in all patients allocated to the HA group within 18 (11, 23) h of ICU admission and conducted for a median duration of 21 (14, 24) h. The intervention was well tolerated except for a trend for a higher rate of aPTT elevation (5 (50%) vs 2 (18%) p = 0.18) and mild (100-150 G/L) thrombocytopenia at day 1 (5 (50%) vs 2 (18%) p = 0.18). Interleukin (IL)-6 plasma levels at randomization were low (< 100 pg/mL) in 10 (48%) patients and elevated (> 1000 pg/mL) in 6 (29%). The median relative reduction in IL-6 at 48 h was 75% (60, 94) in the HA group versus 5% (- 47, 70) in the SOC group (p = 0.06). CONCLUSIONS: In CA survivors at risk of PCAS, HA was feasible, safe and was associated with a nonsignificant reduction in cytokine plasma levels. Future trials are needed to further define the role of HA after CA. Those studies should include cytokine assessment to enrich the study population. TRIAL REGISTRATION: NCT03523039, registered 14 May 2018.

Identification of an optimal threshold to define oliguria in critically ill patients: an observational study.

BACKGROUND: The relevance of current consensus threshold to define oliguria has been challenged by small observational studies. We aimed to determine the optimal threshold to define oliguria in critically-ill patients. METHODS: Cohort study including adult patients admitted within a multi-disciplinary intensive care unit between January 1st 2010 and June 15th 2020. Patients on chronic dialysis or who declined consent were excluded. We extracted hourly urinary output (UO) measurements along with patient's characteristics from electronic medical records and 90-day mortality from the Swiss national death registry. We randomly split our data into a training (80%) and a validation (20%) set. In the training set, we developed multivariable models to assess the relationship between 90-day mortality and the minimum average UO calculated over time windows of 3, 6, 12 and 24 h. Optimal thresholds were determined by visually identifying cut-off values for the minimum average UO below which predicted mortality increased substantially. We tested models' discrimination and calibration on the entire validation set as well as on a subset of patients with oliguria according to proposed thresholds. RESULTS: Among the 15,500 patients included in this analysis (training set: 12,440, validation set: 3110), 73.0% (95% CI [72.3-73.8]) presented an episode of oliguria as defined by consensus criteria (UO < 0.5 ml/kg/h for 6 h). Our models had excellent (AUC > 85% for all time windows) discrimination and calibration. The relationship between minimum average UO and predicted 90-day mortality was nonlinear with an inflexion point at 0.2 ml/kg/h for 3 and 6 h windows and 0.3 ml/kg/h for 12 and 24 h windows. Considering a threshold of < 0.2 ml/kg/h over 6 h, the proportion of patients with an episode of oliguria decreased substantially to 24.7% (95% CI [24.0-25.4]). Contrary to consensus definition, this threshold identified a population with a higher predicted 90-day mortality. CONCLUSIONS: The widely used cut-off for oliguria of 0.5 ml/kg/h over 6 h may be too conservative. A cut-off of 0.2 ml/kg/h over 3 or 6 h is supported by the data and should be considered in further definitions of oliguria.

Validation of a Protocol for Continuous Hemodiafiltration with Regional Citrate Anticoagulation with Omni®.

INTRODUCTION: Omni® (B Braun, Melsungen, Germany) is able to run continuous renal replacement therapy (CRRT) in continuous veno-venous hemofiltration (CVVH), hemodialysis (CVVHD), and hemodiafiltration (CVVHDF) modes. However, to date, there is no validated protocol to guide the use of Omni® in CVVHDF mode with regional citrate anticoagulation (RCA). METHODS: We designed a protocol for CVVHDF-RCA tailored for Omni®. This protocol was tested in patients included in an observational study conducted in our center between January and March 2021. For all study patients, we collected baseline characteristics, laboratory results, CRRT circuit lifespan as well as plasma and effluent samples at 12, 24, 48, and 72 h of CRRT circuit initiation. At each study time point, we computed urea, creatinine, and ß2-microglobulin clearance as well as effluent/blood ratios. Data from circuits in CVVHDF-RCA mode are compared with those in standard therapy (CVVHD-RCA) with the same device. RESULTS: We analyzed ten circuits (5 patients) in CVVHDF-RCA mode and 32 (13 patients) in CVVHD-RCA mode. No adverse events related to the therapy were observed. In CVVHDF-RCA mode, median circuit running time was 68 (IQR 8.1) hours versus 46 (IQR 9.0) in CVVHD mode, p = 0.053. Therapy adaptations (dialysate rate and/or blood flow) were required in one (10%) circuit (15.6% in CVVHD mode, p = 0.56). Compared to CVVHD, CVVHDF was able to achieve similar clearance and effluent/blood ratio for urea, creatinine, and ß2-microglobulin across the entire duration of circuit lifetime. CONCLUSION: The proposed protocol for CVVHDF-RCA for Omni® was associated with similar circuit lifetime, number of required adaptations and clearances to standard CVVHD-RCA. It appears to be safe and feasible.

Epidemiology and outcomes of elderly patients requiring renal replacement therapy in the intensive care unit: an observational study.

BACKGROUND: Renal replacement therapy (RRT) in critically ill patients is associated with high morbidity and mortality. The appropriateness of RRT initiation is sometimes questioned in elderly patients. Therefore, we sought to evaluate the long-term mortality, dialysis dependence and quality of life (QOL) of elderly patients who survived critical illness requiring RRT. METHODS: This is a monocentric observational study including all patients > 55 yo who received RRT for acute kidney injury in our intensive care unit (ICU) between January 2015 and April 2018. At the time of the study (May 2019), we assessed if they were still alive by cross referencing our hospital database and the Swiss national death registry. We sent survivors written information and, subsequently, contacted them over the phone. We obtained their consent for participation, asked about their dialytic status and performed an EQ-5D survey with visual analog scale (VAS). Results were stratified according to their age at the time of ICU admission (G1: "55-65 yo"; G2: "> 65-75 yo" and G3: "> 75 yo"). QOL in G3 patients were compared to G1 and G2 and to predicted values. RESULTS: Among the 352 eligible patients, 171 died during the index hospital admission. After a median follow-up time of 32.7 months (IQR 19.8), a further 62 had died (median time to death for ICU survivors 5.0 (IQR 15.0) months. Hence, 119 (33.6%) patients were still alive at the time of the study. We successfully contacted 96 (80.7%) of them and 83 (69.7%) were included in the study (G1: 24, G2: 44 and G3: 15). Only 6 (7.2%) were RRT dependent. Patients in G3 had lower EQ-5D and VAS scores than those in G1 and G2 (p < 0.01). These scores were also significantly lower than predicted values (p < 0.05). CONCLUSIONS: RRT patients have a very high in-hospital and post discharge mortality. Among survivors, RRT dependency was low. Irrespective of baseline values, patients > 75 yo who survived ICU had a lower QOL than younger patients. It was lower than predicted according to age and sex. The appropriateness of RRT initiation in elderly patients should be discussed according to their pre-existing QOL and frailty.

Complications of Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy: An Observational Study.

INTRODUCTION: Regional citrate anticoagulation (RCA) is the recommended anticoagulation modality for continuous renal replacement therapy (CRRT). RCA was associated with a low rate of complications in randomized controlled trials. However, little is known about the type and rate of complications in real life. We sought to describe complications associated with RCA in comparison with those associated with heparin anticoagulation. METHODS: In our institution, RCA has been the default anticoagulation modality for CRRT in all patients without contraindications since 2013. We have retrospectively reviewed all consecutive patients who received CRRT between January and December 2016 in our institution. For each CRRT session, we have assessed circuit duration, administered dose, as well as therapy-associated complications. Those parameters were compared according to whether the circuit was run in continuous veno-venous hemodialysis (CVVHD) mode with RCA or continuous veno-venous hemofiltration (CVVH) mode with heparin anticoagulation. RESULTS: We analyzed 691 CRRT sessions in 121 patients. Of those 400 (57.9%) were performed in CVVHD-RCA mode and 291 (42.1%) in CVVH-Heparin Mode. Compared with -CVVH-Heparin mode, CVVHD-RCA mode was associated with a longer circuit lifespan (median duration 54.9 interquartile range [IQR 44.6] vs. 15.3 h [IQR 22.4], p < 0.0001). It was associated with a higher rate of metabolic acidosis 77 (20.2%) vs. 18 (7.2%), (p < 0.0001), alkalosis 186 (48.7%) vs. 43 (17.1%), (p= 0.0001), and hypocalcemia 96 (25.07%) vs. 26 events (10.79%), p < 0.0001. However, the majority of these alterations were of benign or moderate severity. Only one possible citrate intoxication was observed. CONCLUSIONS: CVVHD-RCA was associated with a much longer circuit life but an increased rate of minor metabolic complications, in particular acid-base derangements. Some of these complications might have been prevented by therapy adaptation. Medical and nursing staff education is of major importance in the implementation of an RCA protocol.

Epidemiology and outcomes of early versus late septic acute kidney injury in critically ill patients: A retrospective cohort study.

BACKGROUND: It was recently proposed to distinguish early from late sepsis-associated acute kidney injury (SA-AKI). We aimed to determine the relative frequency of these entities in critically ill patients and to describe their characteristics and outcomes. METHODS: We included in this retrospective cohort study all adult patients admitted for sepsis in a tertiary ICU between 2010 and 2020. We excluded those on chronic dialysis or without consent. We extracted serum creatinine, hourly urinary output, and clinical and socio-demographic data from medical records until day 7 or ICU discharge. AKI presence and characteristics were assessed daily using KDIGO criteria. We compared patients with early (occurring within 2 days of admission) or late (occurring between day 2 and day 7) SA-AKI. We conducted sensitivity analyses using different definitions for early/late SA-AKI. RESULTS: Among 1835 patients, 1660 (90%) fulfilled SA-AKI criteria. Of those, 1610 (97%) had early SA-AKI, and 50 (3%) had late SA-AKI. Similar proportions were observed when only considering AKI with elevated sCr (71% vs. 3%), severe AKI (67% vs. 6%), or different time windows for early SA-AKI. Compared with early SA-AKI patients, those with late SA-AKI were younger (median age [IQR] 59 [49-70] vs. 69 [58-76] years, p < 0.001), had lower Charlson comorbidity index (3 [1-5] vs. 5 [3-7], p < 0.001) and lower SAPSII scores (41 [34-50] vs. 53 [43-64], p < 0.001). They had similar (24% vs. 26%, p = 0.75) in-hospital mortality. CONCLUSIONS: AKI is almost ubiquitous in septic critically ill patients and present within two days of admission. The timing from ICU admission might not be relevant to distinguish different phenotypes of SA-AKI. ETHICS APPROVAL: Ethics Committee Vaud, Lausanne, Switzerland (n°2017-00008).

Kinetics of small and middle molecule clearance during continuous hemodialysis.

Regional citrate anticoagulation (RCA) enables prolonged continuous kidney replacement therapy (CKRT) filter lifespan. However, membrane diffusive performance might progressively decrease and remain unnoticed. We prospectively evaluated the kinetics of solute clearance and factors associated with decreased membrane performance in 135 consecutive CKRT-RCA circuits (35 patients). We recorded baseline patients' characteristics and clinical signs of decreased membrane performance. We calculated effluent/serum ratios (ESR) as well as respective clearances for urea, creatinine and ß2-microglobuline at 12, 24, 48 and 72 h after circuit initiation. Using mixed-effects logistic regression model analyses, we assessed the effect of time on those values and determined independent predictors of decreased membrane performance as defined by an ESR for urea < 0.81. We observed a minor but statistically significant decrease in both ESR and solute clearance across the duration of therapy for all three solutes. We observed decreased membrane performance in 31 (23%) circuits while clinical signs were present in 19 (14.1%). The risk of decreased membrane performance significantly increased over time: 1.8% at T1 (p = 0.16); 7.3% at T2 (p = 0.01); 15.7% at T3 (p = 0.001) and 16.4% at T4 (p < 0.003). Four factors present within 24 h of circuit initiation were independently associated with decreased membrane performance: arterial blood bicarbonate level (OR 1.50; p < 0.001), activated partial thromboplastin time (aPTT; OR = 0.93; p = 0.02), fibrinogen level (OR 6.40; p = 0.03) and Charlson score (OR 0.10; p < 0.01). COVID-19 infection was not associated with increased risk of decreased membrane performance. Regular monitoring of ESR might be appropriate in selected patients undergoing CKRT.

Association of Oliguria With Acute Kidney Injury Diagnosis, Severity Assessment, and Mortality Among Patients With Critical Illness.

Importance: The current definition and staging of acute kidney injury (AKI) considers alterations in serum creatinine (sCr) level and urinary output (UO). However, the relevance of oliguria-based criteria is disputed. Objective: To determine the contribution of oliguria, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, to AKI diagnosis, severity assessment, and short- and long-term outcomes. Design, Setting, and Participants: This cohort study included adult patients admitted to a multidisciplinary intensive care unit from January 1, 2010, to June 15, 2020. Patients receiving long-term dialysis and those who declined consent were excluded. Daily sCr level and hourly UO measurements along with sociodemographic characteristics and severity scores were extracted from electronic medical records. Long-term mortality was assessed by cross-referencing the database with the Swiss national death registry. The onset and severity of AKI according to the KDIGO classification was determined using UO and sCr criteria separately, and their agreement was assessed. Main Outcomes and Measures: Using a multivariable model accounting for baseline characteristics, severity scores, and sCr stages, the association of UO criteria with 90-day mortality was evaluated. Sensitivity analyses were conducted to assess how missing sCr, body weight, and UO values, as well as different sCr baseline definitions and imputations methods, would affect the main results. Results: Among the 15 620 patients included in the study (10 330 men [66.1%] with a median age of 65 [IQR, 53-75] years, a median Simplified Acute Physiology Score II score of 40.0 [IQR, 30.0-53.0], and a median follow-up of 67.0 [IQR, 34.0-100.0] months), 12 143 (77.7%) fulfilled AKI criteria. Serum creatinine and UO criteria had poor agreement on AKI diagnosis and staging (Cohen weighted κ, 0.36; 95% CI, 0.35-0.37; P < .001). Compared with the isolated use of sCr criteria, consideration of UO criteria enabled identification of AKI in 5630 patients (36.0%). Those patients had a higher 90-day mortality than patients without AKI (724 of 5608 [12.9%] vs 288 of 3462 [8.3%]; P < .001). On multivariable analysis accounting for sCr stage, comorbidities, and illness severity, UO stages 2 and 3 were associated with a higher 90-day mortality (odds ratios, 2.4 [95% CI, 1.6-3.8; P < .001] and 6.2 [95% CI, 3.7-10.5; P < .001], respectively). These results remained significant in all sensitivity analyses. Conclusions and Relevance: The findings of this cohort study suggest that oliguria lasting more than 12 hours (KDIGO stage 2 or 3) has major AKI diagnostic implications and is associated with outcomes irrespective of sCr elevations.