High-volume hemofiltration does not protect human kidney endothelial and tubular epithelial cells from septic plasma-induced injury.

High volume hemofiltration (HVHF) could remove from plasma inflammatory mediators involved in sepsis-associated acute kidney injury (SA-AKI). The IVOIRE trial did not show improvements of outcome and organ dysfunction using HVHF. The aim of this study was to evaluate in vitro the biological effects of plasma of patients treated by HVHF or standard volume hemofiltration (SVHF). We evaluated leukocyte adhesion, apoptosis and functional alterations of endothelial cells (EC) and tubular epithelial cells (TEC). In vitro data were correlated with plasma levels of TNF-α, Fas-Ligand (FasL), CD40-Ligand (CD40L), von Willebrand Factor (vWF) and endothelial-derived microparticles. An experimental model of in vitro hemofiltration using LPS-activated blood was established to assess cytokine mass adsorption during HVHF or SVHF. Plasma concentrations of TNF-ɑ, FasL, CD40L and von Willebrand Factor (vWF) were elevated at the start (d1h0) of both HVHF and SVHF, significantly decreased after 6 h (d1h6), remained stable after 12 h (d1h12) and then newly increased at 48 h (d3h0). Plasma levels of all these molecules were similar between HVHF- and SVHF-treated patients at all time points considered. In addition, the levels of endothelial microparticles remained always elevated, suggesting the presence of a persistent microvascular injury. Plasma from septic patients induced leukocyte adhesion on EC and TEC through up-regulation of adhesion receptors. Moreover, on EC, septic plasma induced a cytotoxic and anti-angiogenic effect. On TEC, septic plasma exerted a direct pro-apoptotic effect via Fas up-regulation and caspase activation, loss of polarity, altered expression of megalin and tight junction molecules with an impaired ability to internalize albumin. The inhibition of plasma-induced cell injury was concomitant to the decrease of TNF-α, Fas-Ligand and CD40-Ligand levels. The protective effect of both HVHF and SVHF was time-limited, since a further increase of circulating mediators and plasma-induced cell injury was observed after 48 h (d3h0). No significant difference of EC/TEC damage were observed using HVHF- or SVHF-treated plasma. The in vitro hemofiltration model confirmed the absence of a significant modulation of cytokine adsorption between HVHF and SVHF. In comparison to SVHF, HVHF did not increase inflammatory cytokine clearance and did not reverse the detrimental effects of septic plasma-induced EC and TEC injury. Further studies using adsorptive membranes are needed to evaluate the potential role of high dose convective therapies in the limitation of the harmful activity of plasma soluble factors involved in SA-AKI.Trial registration IVOIRE randomized clinical trial; ClinicalTrials.gov (NCT00241228) (18/10/2005).

The Use of Adsorption in Extracorporeal Liver Support: The Double Plasma Molecular Adsorption System (DPMAS).

Liver failure in the intensive care unit (ICU), whether acute or acute-on-chronic, remains a serious condition with reduced functions, various metabolite and toxin accumulation in the systemic circulation, and a high mortality rate. While transplantation remains the treatment of choice, the lack of organ transplants necessitates finding alternative solutions. Within the last years, several therapies aiming to support liver function have been developed in order to serve as a bridge to liver transplantation or as replacement therapy, allowing regeneration of the injured liver. In those therapies, nonbiological extracorporeal liver support devices are the most widely used, mainly based on detoxification by eliminating accumulated toxins notably by adsorption on specific membranes and/or with plasmapheresis. One of the most recent techniques is the double plasma molecular adsorption system combining plasma filtration and two specific adsorption membranes, which is largely described and studied in this chapter. This technique seems promising to remove deleterious toxins, cytokines and bilirubin in particular, is fairly simple to use, does not require a specific machine (it works on continuous renal replacement therapy machines), and has given encouraging results in the pilot studies published recently, in association with plasmapheresis or alone. However, further studies and evaluations are needed before this technique can be used routinely in ICU.

Accuracy of clinicians' ability to predict the need for renal replacement therapy: a prospective multicenter study.

PURPOSE: Identifying patients who will receive renal replacement therapy (RRT) during intensive care unit (ICU) stay is a major challenge for intensivists. The objective of this study was to evaluate the performance of physicians in predicting the need for RRT at ICU admission and at acute kidney injury (AKI) diagnosis. METHODS: Prospective, multicenter study including all adult patients hospitalized in 16 ICUs in October 2020. Physician prediction was estimated at ICU admission and at AKI diagnosis, according to a visual Likert scale. Discrimination, risk stratification and benefit of physician estimation were assessed. Mixed logistic regression models of variables associated with risk of receiving RRT, with and without physician estimation, were compared. RESULTS: Six hundred and forty-nine patients were included, 270 (41.6%) developed AKI and 77 (11.8%) received RRT. At ICU admission and at AKI diagnosis, a model including physician prediction, the experience of the physician, SOFA score, serum creatinine and diuresis to determine need for RRT performed better than a model without physician estimation with an area under the ROC curve of 0.90 [95% CI 0.86-0.94, p < 0.008 (at ICU admission)] and 0.89 [95% CI 0.83-0.93, p = 0.0014 (at AKI diagnosis)]. In multivariate analysis, physician prediction was strongly associated with the need for RRT, independently of creatinine levels, diuresis, SOFA score and the experience of the doctor who made the prediction. CONCLUSION: As physicians are able to stratify patients at high risk of RRT, physician judgement should be taken into account when designing new randomized studies focusing on RRT initiation during AKI.

Characterising acute kidney injury: The complementary roles of biomarkers of renal stress and renal function.

PURPOSE: Although epidemiological studies have enhanced our understanding of acute kidney injury, defining the biologic processes corresponding to the clinical phenotype remains challenging. We have examined biomarkers associated with renal stress plus markers of glomerular function to assess whether this approach may aid prediction of AKI or other relevant endpoints. MATERIALS & METHODS: Urinary [TIMP-2]·[IGFBP7], serum creatinine, plasma cystatin C and plasma proenkephalin 119-159 2 were analyzed in patients enrolled in the prospective, international, Sapphire study. Heterogenous critically ill patients (n = 723) were examined with a primary endpoint of development of KDIGO stage 2-3 within 12 h and a secondary endpoint of major adverse kidney events at 30 days (MAKE30). RESULTS: 100 patients (14%) reached the primary endpoint. Markers of renal stress outperformed those associated with glomerular function. Combining [TIMP-2]•[IGFBP7] with serum creatinine, but not the other functional markers, significantly (p = 0.02) increased the area under the ROC curve (AUC) from 0.80 (0.76-0.84) to 0.85 (0.81-0.89). In patients who did not develop AKI, all markers of glomerular filtration, but not [TIMP-2]·[IGFBP7], were significantly elevated in patients with a history of CKD (p < 0.05). CONCLUSIONS: The combination of cell-cycle arrest biomarkers, TIMP-2 and IGFBP7, with serum creatinine but not cystatin C or PENK improved risk stratification for the development of stage 2 or 3 AKI over [TIMP-2]·[IGFBP7] alone.

Guidelines for the management of patients with severe acute pancreatitis, 2021.

OBJECTIVE: To provide guidelines for the management of the intensive care patient with severe acute pancreatitis. DESIGN: A consensus committee of 22 experts was convened. A formal conflict-of-interest (COI) policy was developed at the beginning of the process and enforced throughout. The entire guideline construction process was conducted independently of any industrial funding (i.e. pharmaceutical, medical devices). The authors were required to follow the rules of the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) system to guide assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised. METHODS: The most recent SFAR and SNFGE guidelines on the management of the patient with severe pancreatitis were published in 2001. The literature now is sufficient for an update. The committee studied 14 questions within 3 fields. Each question was formulated in a PICO (Patients Intervention Comparison Outcome) format and the relevant evidence profiles were produced. The literature review and recommendations were made according to the GRADE® methodology. RESULTS: The experts' synthesis work and their application of the GRADE® method resulted in 24 recommendations. Among the formalised recommendations, 8 have high levels of evidence (GRADE 1+/-) and 12 have moderate levels of evidence (GRADE 2+/-). For 4 recommendations, the GRADE method could not be applied, resulting in expert opinions. Four questions did not find any response in the literature. After one round of scoring, strong agreement was reached for all the recommendations. CONCLUSIONS: There was strong agreement among experts for 24 recommendations to improve practices for the management of intensive care patients with severe acute pancreatitis.

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.

Guidelines for the choice of intravenous fluids for vascular filling in critically ill patients, 2021.

PURPOSE: To provide recommendations for the appropriate choice of fluid therapy for resuscitation of critically ill patients. DESIGN: A consensus committee of 24 experts from the French Society of Anaesthesia and Intensive Care Medicine (Société française d'anesthésie et de réanimation, SFAR) and the French Society of Emergency Medicine (Société française de médecine d'urgence, SFMU) was convened. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. The entire guideline elaboration process was conducted independently of any industry funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide their assessment of quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised. Some recommendations were left ungraded. METHODS: Four fields were defined: patients with sepsis or septic shock, patients with haemorrhagic shock, patients with acute brain failure, and patients during the peripartum period. For each field, the panel focused on two questions: (1) Does the use of colloids, as compared to crystalloids, reduce morbidity and mortality, and (2) Does the use of some specific crystalloids effectively reduce morbidity and mortality. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. The analysis of the literature and the recommendations were then conducted according to the GRADE methodology. RESULTS: The SFAR/SFMU guideline panel provided nine statements on the appropriate choice of fluid therapy for resuscitation of critically ill patients. After two rounds of rating and various amendments, strong agreement was reached for 100% of the recommendations. Out of these recommendations, two have a high level of evidence (Grade 1 +/-), six have a moderate level of evidence (Grade 2 +/-), and one is based on expert opinion. Finally, no recommendation was formulated for two questions. CONCLUSIONS: Substantial agreement among experts has been obtained to provide a sizable number of recommendations aimed at optimising the choice of fluid therapy for resuscitation of critically ill patients.

Prognostic Impact of Early Recovering Acute Kidney Injury Following Liver Transplantation: A Multicenter Retrospective Study.

BACKGROUND: Acute kidney injury (AKI) is a common complication after liver transplantation (LT), but the specific impact of rapidly resolving AKI is not elucidated. This study investigates the factors associated with early recovery from AKI and its association with post-LT outcomes. METHODS: Retrospective analysis of 441 liver transplant recipients with end-stage liver disease without pretransplant renal impairment. AKI was defined according to Kidney Disease Improving Global Outcomes criteria and early renal recovery by its disappearance within 7 d post-LT. RESULTS: One hundred forty-six patients (32%) developed a post-LT AKI, of whom 99 (69%) recovered early and 45 (31%) did not. Factors associated with early recovery were Kidney Disease Improving Global Outcomes stage 1 (odds ratio [OR],14.11; 95% confidence interval [CI], 5.59-40.22; P < 0.0001), minimum prothrombin time >50 % (OR, 4.50; 95% CI, 1.67-13.46; P = 0.003) and aspartate aminotransferase peak value <1000 U/L (OR, 4.07; 95% CI, 1.64-10.75; P = 0.002) within 48 h post-LT. Patients with early recovery had a renal prognosis similar to that of patients without AKI with no difference in estimated glomerular filtration rate between day 7 and 1 y. Their relative risk of developing chronic kidney disease was 0.88 (95% CI, 0.55-1.41; P = 0.6) with survival identical to patients without AKI and better than patients without early recovery (P < 0.0001). CONCLUSIONS: Most patients with post-LT AKI recover early and have a similar renal prognosis and survival to those without post-LT AKI. Factors associated with early renal recovery are related to the stage of AKI, the extent of liver injury, and the early graft function. Patients at risk of not recovering may benefit the most from perioperative protective strategies, particularly those aimed at minimizing the adverse effects of calcineurin inhibitors.

High mean arterial pressure target to improve sepsis-associated acute kidney injury in patients with prior hypertension: a feasibility study.

BACKGROUND: The optimal mean arterial pressure (MAP) in cases of septic shock is still a matter of debate in patients with prior hypertension. An MAP between 75 and 85 mmHg can improve glomerular filtration rate (GFR) but its effect on tubular function is unknown. We assessed the effects of high MAP level on glomerular and tubular renal function in two intensive care units of a teaching hospital. Inclusion criteria were patients with a history of chronic hypertension and developing AKI in the first 24 h of septic shock. Data were collected during two 6 h periods of MAP regimen administered consecutively after haemodynamic stabilisation in an order depending on the patient's admission unit: a high-target period (80-85 mmHg) and a low-target period (65-70 mmHg). The primary endpoint was the creatinine clearance (CrCl) calculated from urine and serum samples at the end of each MAP period by the UV/P formula. RESULTS: 26 patients were included. Higher urine output (+0.2 (95%:0, 0.4) mL/kg/h; P = 0.04), urine sodium (+6 (95% CI 0.2, 13) mmol/L; P = 0.04) and lower serum creatinine (- 10 (95% CI - 17, - 3) µmol/L; P = 0.03) were observed during the high-MAP period as compared to the low-MAP period, resulting in a higher CrCl (+25 (95% CI 11, 39) mL/mn; P = 0.002). The urine creatinine, urine-plasma creatinine ratio, urine osmolality, fractional excretion of sodium and urea showed no significant variation. The KDIGO stage at inclusion only interacted with serum creatinine variation and low level of sodium excretion at inclusion did not interact with these results. CONCLUSIONS: In the early stage of sepsis-associated AKI, a high-MAP target in patients with a history of hypertension was associated with a higher CrCl, but did not affect the kidneys' ability to concentrate urine, which may reflect no effect on tubular function.

French multicentre observational study on SARS-CoV-2 infections intensive care initial management: the FRENCH CORONA study.

AIM: Describing acute respiratory distress syndrome patterns, therapeutics management, and outcomes of ICU COVID-19 patients and indentifying risk factors of 28-day mortality. METHODS: Prospective multicentre, cohort study conducted in 29 French ICUs. Baseline characteristics, comorbidities, adjunctive therapies, ventilatory support at ICU admission and survival data were collected. RESULTS: From March to July 2020, 966 patients were enrolled with a median age of 66 (interquartile range 58-73) years and a median SAPS II of 37 (29-48). During the first 24 h of ICU admission, COVID-19 patients received one of the following respiratory supports: mechanical ventilation for 559 (58%), standard oxygen therapy for 228 (24%) and high-flow nasal cannula (HFNC) for 179 (19%) patients. Overall, 721 (75%) patients were mechanically ventilated during their ICU stay. Prone positioning and neuromuscular blocking agents were used in 494 (51%) and 460 (48%) patients, respectively. Bacterial co-infections and ventilator-associated pneumonia were diagnosed in 79 (3%) and 411 (43%) patients, respectively. The overall 28-day mortality was 18%. Age, pre-existing comorbidities, severity of respiratory failure and the absence of antiviral therapy on admission were identified as independent predictors of 28-day outcome. CONCLUSION: Severity of hypoxaemia on admission, older age (> 70 years), cardiovascular and renal comorbidities were associated with worse outcome in COVID-19 patients. Antiviral treatment on admission was identified as a protective factor for 28-day mortality. Ascertaining the outcomes of critically ill COVID-19 patients is crucial to optimise hospital and ICU resources and provide the appropriate intensity level of care.