Initiation of continuous renal replacement therapy versus intermittent hemodialysis in critically ill patients with severe acute kidney injury: a secondary analysis of STARRT-AKI trial.

BACKGROUND: There is controversy regarding the optimal renal-replacement therapy (RRT) modality for critically ill patients with acute kidney injury (AKI). METHODS: We conducted a secondary analysis of the STandard versus Accelerated Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial to compare outcomes among patients who initiated RRT with either continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD). We generated a propensity score for the likelihood of receiving CRRT and used inverse probability of treatment with overlap-weighting to address baseline inter-group differences. The primary outcome was a composite of death or RRT dependence at 90-days after randomization. RESULTS: We identified 1590 trial participants who initially received CRRT and 606 who initially received IHD. The composite outcome of death or RRT dependence at 90-days occurred in 823 (51.8%) patients who commenced CRRT and 329 (54.3%) patients who commenced IHD (unadjusted odds ratio (OR) 0.90; 95% confidence interval (CI) 0.75-1.09). After balancing baseline characteristics with overlap weighting, initial receipt of CRRT was associated with a lower risk of death or RRT dependence at 90-days compared with initial receipt of IHD (OR 0.81; 95% CI 0.66-0.99). This association was predominantly driven by a lower risk of RRT dependence at 90-days (OR 0.61; 95% CI 0.39-0.94). CONCLUSIONS: In critically ill patients with severe AKI, initiation of CRRT, as compared to IHD, was associated with a significant reduction in the composite outcome of death or RRT dependence at 90-days.

Specific nutrition and metabolic characteristics of critically ill patients with persistent COVID-19.

BACKGROUND: Little is known about metabolic and nutrition characteristics of patients with coronavirus disease 2019 (COVID-19) and persistent critical illness. We aimed to compare those characteristics in patients with PCI and COVID-19 and patients without COVID-19 infection (non-CO)-primarily, their energy balance. METHODS: This is a prospective observational study including two consecutive cohorts, defined as needing intubation for >10 days. We collected demographic data, severity scores, nutrition variables, length of stay, and mortality. RESULTS: Altogether, 104 patients (52 per group) were included (59 ± 14 years old [mean ± SD], 75% men) between July 2019 and May 2020. SAPSII, Nutrition Risk Screening (NRS) score, proportion of obese patients, duration of intubation (18.2 ± 11.7 days), and mortality rates were similar. Patients with COVID-19 (vs non-CO) had lower SOFA scores (P = 0.013) and more frequently needed prone position (P < 0.0001) and neuromuscular blockade (P < 0.0001): lengths of ICU (P = 0.03) and hospital stays were shorter (P < 0.0001). Prescribed energy targets were below those of the ICU protocol. The energy balance of patients with COVID-19 was significantly more negative after day 10. Enteral nutrition (EN) started earlier (P < 0.0001). During the first 10 days, COVID-19 patients received more lipid (propofol sedation) and less protein. Higher admission C-reactive protein (P = 0.002) decreased faster (P < 0.001). Whereas intestinal function was characterized by constipation in both groups during the first 10 days, diarrhea was less common in patients with COVID-19 thereafter. CONCLUSION: Compared with non-CO patients, COVID-19 patients were not more obese, had lower SOFA scores, and were fed more rapidly with EN, because of a more normal gastrointestinal function possibly due to fewer non-respiratory organ failures: their energy balances were more negative after the first 10 days. Propofol sedation reduced protein delivery.

Magnitude of gluconeogenesis and endogenous glucose production: are they predictable in clinical settings?

INTRODUCTION: Regulation of endogenous glucose production (EGP) is essential for glucose homeostasis. It includes gluconeogenesis (GNG) from non-carbohydrate substrates and hepatic glycogenolysis. Both these pathways are dysregulated in acute stress, but the magnitude of this deregulation cannot be assessed in clinical practice. The study aims at identifying clinically available variables predictive of EGP and GNG magnitude by modeling routinely available data. METHODS: This exploratory study is based on the data from the Supplemental Parenteral Nutrition study 2 (SPN2), which measured EGP and GNG at days 4 and 10 in 23 critically ill patients. The correlation between EGP and GNG and 83 potential clinical indicators were explored, using single-stage and multivariate analysis. RESULTS: On single-stage analysis, the strongest correlations were noradrenaline dose at day 4 with GNG (R = 0.71; P = 0.0004) and Nutrition risk screening score (NRS) with EGP (R = 0.42; P = 0.05). At day 10, VO2 (R = 0.59, P = 0.04) was correlated with GNG and VCO2 with EGP (R = 0.85, P = 0.00003). Cumulated insulin dose between days 5 and 9 was correlated to EGP at day 10 (R = 0.55, P = 0.03). Our multivariate model could predict EGP at day 4 (VCO2, glucose and energy intake) with an error coefficient (e.c.) between 7.8% and 23.4% (minimal and maximal error), and GNG at day 10 (age, mean and basal blood glucose), with an e.c. of 18.5% and 29.9%. GNG at day 4 and EGP at day 10 could not be predicted with an e.c. < 40%. CONCLUSION: This preliminary exploratory study shows that GNG and EGP have different predictors on days 4 and 10; EGP is more correlated with the metabolic level, while GNG is dependent on external factors. Nevertheless, a bundle of variables could be identified to empirically assess the magnitude of both values. Our results suggest that a robust model might be built, but requires a prospective study including a larger number of patients.

Pharmacokinetics of anti-infective agents during CytoSorb hemoadsorption.

Cytokine hemoadsorption might be beneficial in patients with sepsis. However, its effect on anti-infective agents' disposition remains largely unknown. We sought to determine the influence of hemoadsorption on the pharmacokinetics of common anti-infective agents. This is an interventional experimental study, conducted in 24 healthy pigs. Animals were randomly allocated to either hemoadsorption (cases) or sham extracorporeal circuit (controls) and to drug combinations (3 cases and 3 controls for each combination). Hemoadsorption was performed with CytoSorb (CytoSorbents Corporation, USA). We evaluated 17 drugs (clindamycin, fluconazole, linezolid, meropenem, piperacillin, anidulafungin, ganciclovir, clarithromycin, posaconazole, teicoplanin, tobramycin, ceftriaxone, ciprofloxacin, metronidazole, liposomal amphotericin B, flucloxacillin and cefepime). Repeated blood sampling from the extracorporeal circulation (adsorber inlet/outlet, sham circuit) was performed over six hours following administration. Total clearance and adsorber-specific clearance were computed. Hemoadsorption was associated with increased clearance of all study drugs, except ganciclovir. Its impact on total body clearance was considered as moderate for fluconazole (282%) and linezolid (115%), mild for liposomal amphotericin B (75%), posaconazole (32%) and teicoplanine (31%) and negligible for all other drugs. Hemoadsorber clearance declined over time, with even delayed desorption for beta-lactams. It was moderately correlated with drug's lipophilicity (p = 0.01; r2 = 0.43). Hemoadsorption with CytoSorb appears to increase to a clinically significant extent the clearance of five among 17 tested anti-infectives. Studies in human patients are required to confirm the need for dosage adjustment of these agents.

Amino acids and vitamins status during continuous renal replacement therapy: An ancillary prospective observational study of a randomised control trial.

BACKGROUND: Continuous renal replacement therapy (CRRT) is associated with micronutrients loss. Current recommendations are to administer 1-1.5g/kg/day of proteins during CRRT. We aim to evaluate the net effect of CRRT on amino acids (AA), vitamins A and C (Vit A, Vit C) levels. METHODS: This is a prospective observational study embedded within a randomised controlled trial comparing two CRRT doses in patients with septic shock. CRRT was provided in continuous veno-venous haemofiltration mode at a dose of either 35ml/kg/h or 70ml/kg/h. All patients received parenteral nutrition with standard trace elements and vitamins (protein intake 1g/kg/d). We measured serum levels of glutamine, valine and alanine as well as Vit A and Vit C upon randomisation, study day four and eight. In addition, we measured a larger panel of AA in a subset of 11 patients. RESULTS: We included 30 patients (17 allocated to 70ml/kg/h and 13 to 35ml/kg/h CRRT). Before CRRT initiation, mean plasma levels of glutamine and valine, Vit A and Vit C were low. CRRT was not associated with any significant change in AA levels except for a decrease in cystein. It was associated with an increase in Vit A and a decrease in Vit C levels. CRRT dose had no impact on those nutrients blood levels. CONCLUSIONS: Irrespective of dose, CRRT was associated with a decrease in cysteine and Vit C and an increase in Vit A with no significant change in other AA. Further studies should focus on lean mass wasting during CRRT.

Real-time glomerular filtration rate: improving sensitivity, accuracy and prognostic value in acute kidney injury.

PURPOSE OF REVIEW: Acute kidney injury (AKI) is common and associated with high patient mortality, and accelerated progression to chronic kidney disease. Our ability to diagnose and stratify patients with AKI is paramount for translational progress. Unfortunately, currently available methods have major pitfalls. Serum creatinine is an insensitive functional biomarker of AKI, slow to register the event and influenced by multiple variables. Cystatin C, a proposed alternative, requires long laboratory processing and also lacks specificity. Other techniques are either very cumbersome (inuline, iohexol) or involve administration of radioactive products, and are therefore, not applicable on a large scale. RECENT FINDINGS: The development of two optical measurement techniques utilizing novel minimally invasive techniques to quantify kidney function, independent of serum or urinary measurements is advancing. Utilization of both one and two compartmental models, as well as continuous monitoring, are being developed. SUMMARY: The clinical utility of rapid GFR measurements in AKI patients remains unknown as these disruptive technologies have not been tested in studies exploring clinical outcomes. However, these approaches have the potential to improve our understanding of AKI and clinical care. This overdue technology has the potential to individualize patient care and foster therapeutic success in AKI.

[Regional citrate anticoagulation for continuous renal replacement therapy]. / Anticoagulation régionale au citrate pour l'épuration extrarénale continue.

Regional citrate anticoagulation (RCA) is currently the recommended anticoagulation modality for continuous renal replacement therapy. Indeed, compared with systemic heparinization, RCA is associated with a lower risk of bleeding, a longer circuit lifespan and a decrease nursing workload. However, RCA requires a strict protocol to be followed, as it might be associated with potentially severe complications, such as citrate accumulation. Citrate accumulation is rare and usually associated with specific situations : severe circulatory shock, liver failure and mitochondrial dysfunction. According to centers' expertise, these situations might represent contra-indications to RCA. This review presents RCA, its mode of action, associated risks and proposes an algorithm for patients' selection.

L'anticoagulation régionale au citrate (ARC) est actuellement la modalité de choix pour l'épuration extrarénale continue. Par rapport à une anticoagulation systémique par héparine, l'ARC est associée à un moindre risque hémorragique, une plus longue durée de vie des circuits et une moindre charge de travail infirmière. Cependant, elle nécessite de mettre en place un protocole strict, car elle peut être associée à des complications potentiellement graves dont la plus redoutée est l'intoxication au citrate. Cette dernière est rare et ne survient a priori que lors de certaines situations à risque : état de choc sévère, insuffisance hépatique ou dysfonction mitochondriale. En fonction de l'expertise des centres, ces situations peuvent représenter des contre-indications à l'ARC. Cet article présente l'ARC, son mode d'action, les risques associés et propose un algorithme de sélection des patients.

Adequacy of stress ulcer prophylaxis prescription in the intensive care unit: an observational study.

PURPOSE: Stress ulcer prophylaxis prescriptions might not be sufficiently challenged throughout a patient's stay in an intensive care unit (ICU) and might be erroneously maintained after ICU discharge. This study aimed to determine (1) stress ulcer prophylaxis adequacy in ICU and (2) the proportion of patients receiving inappropriate stress ulcer prophylaxis after ICU discharge. MATERIAL AND METHODS: This was an observational, single centre study (University Hospital Lausanne, Switzerland). All patients without a previous indication for acid-suppressive therapy and admitted to our ICU for >24 hrs during a two-month period were included. The adequacy of stress ulcer prophylaxis prescriptions according to our guidelines was assessed. We then assessed stress ulcer prophylaxis prescriptions and their adequacy on ICU and hospital discharge, as well as the costs associated with inadequate prescription. RESULTS: Of the 372 patients admitted during the study period, 140 (855 patient-days) fulfilled the inclusion criteria. Of these, 130 (92.9%) received stress ulcer prophylaxis in the ICU (796 [93.1%] patient-days). Stress ulcer prophylaxis consisted of esomeprazole in 686 (86.2%) patient-days. Overall, stress ulcer prophylaxis was inadequate in 558 (65.3%) patient-days, mostly because it was prescribed while not indicated (543 patient-days [63.5%]). On ICU discharge, stress ulcer prophylaxis prescription was inadequately maintained in 55 patients (51.9% of survivors). Similarly, stress ulcer prophylaxis was inadequately maintained on hospital discharge in 30 (28% of survivors) patients. We estimated the in-hospital cost of inadequate stress ulcer prophylaxis prescription as approximately CHF 2870 per year. Outpatient therapy maintenance would be associated with additional costs ranging from CHF 33,912 to 92,692 (EUR 31,832 to 87,012) for each additional year they receive the therapy, depending on the medication used. CONCLUSIONS: The adequacy of stress ulcer prophylaxis in the ICU is low. In addition, the prescription is frequently continued after ICU and many patients are even discharged home with inadequate acid-suppressive therapy.    .

Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury.

BACKGROUND: Acute kidney injury is common in critically ill patients, many of whom receive renal-replacement therapy. However, the most effective timing for the initiation of such therapy remains uncertain. METHODS: We conducted a multinational, randomized, controlled trial involving critically ill patients with severe acute kidney injury. Patients were randomly assigned to receive an accelerated strategy of renal-replacement therapy (in which therapy was initiated within 12 hours after the patient had met eligibility criteria) or a standard strategy (in which renal-replacement therapy was discouraged unless conventional indications developed or acute kidney injury persisted for >72 hours). The primary outcome was death from any cause at 90 days. RESULTS: Of the 3019 patients who had undergone randomization, 2927 (97.0%) were included in the modified intention-to-treat analysis (1465 in the accelerated-strategy group and 1462 in the standard-strategy group). Of these patients, renal-replacement therapy was performed in 1418 (96.8%) in the accelerated-strategy group and in 903 (61.8%) in the standard-strategy group. At 90 days, death had occurred in 643 patients (43.9%) in the accelerated-strategy group and in 639 (43.7%) in the standard-strategy group (relative risk, 1.00; 95% confidence interval [CI], 0.93 to 1.09; P = 0.92). Among survivors at 90 days, continued dependence on renal-replacement therapy was confirmed in 85 of 814 patients (10.4%) in the accelerated-strategy group and in 49 of 815 patients (6.0%) in the standard-strategy group (relative risk, 1.74; 95% CI, 1.24 to 2.43). Adverse events occurred in 346 of 1503 patients (23.0%) in the accelerated-strategy group and in 245 of 1489 patients (16.5%) in the standard-strategy group (P<0.001). CONCLUSIONS: Among critically ill patients with acute kidney injury, an accelerated renal-replacement strategy was not associated with a lower risk of death at 90 days than a standard strategy. (Funded by the Canadian Institutes of Health Research and others; STARRT-AKI ClinicalTrials.gov number, NCT02568722.).

Cardiogenic shock elicits acute inflammation, delayed eosinophilia, and depletion of immune cells in most severe cases.

Patients with cardiogenic shock (CS) display systemic inflammation and a high rate of infections, suggesting important immune disturbances. To explore the immune response to CS, we prospectively measured, in 24 consecutive CS patients, differential white blood cell (WBC) counts and the cytokines IL-1ß, IL-5, IL-6, IL-10, TNFα, IFNγ, MCP-1 and eotaxin (CCL11), at Day 1 (T1), day 3 (T2) and day 6-8 (T3). Secondary infections and their influence on cytokines and WBCs were determined. CS induced early (T1) neutrophilia and elevated levels of IL-6, IL-10 and MCP-1, correlating with shock severity. The eosinophil chemoattractant eotaxin was elevated at T1 and decreased thereafter, and a progressive rise of blood eosinophils was noted over time. Patients with the most severe shock had reduced lymphocytes and monocytes at T2 and T3. Sixty-two percent of patients developed an infection, which did not alter the profile of immune response, except from higher IL-6 levels at T2. Therefore, CS elicits an acute pro-inflammatory response, followed by a delayed increase in blood eosinophils, consistent with the development of a tissue repair response, as well as depletion of immune cells in the most severely affected patients, which might predispose to secondary infections.

Early Osmotherapy in Severe Traumatic Brain Injury: An International Multicenter Study.

The optimal osmotic agent to treat intracranial hypertension in patients with severe traumatic brain injury (TBI) remains uncertain. We aimed to test whether the choice of mannitol or hypertonic saline (HTS) as early (first 96 h) osmotherapy in these patients might be associated with a difference in mortality. We retrospectively analyzed data from 2015 from 14 tertiary intensive care units (ICUs) in Australia, UK, and Europe treating severe TBI patients with intracranial pressure (ICP) monitoring and compared mortality in those who received mannitol only versus HTS only. We performed multi-variable analysis adjusting for site and illness severity (Injury Severity Score, extended IMPACT score, and mean ICP over the first 96 h) using Cox proportional hazards regression. We collected data on 262 patients and compared patients who received early osmotherapy with mannitol alone (n = 46) with those who received HTS alone (n = 46). Mannitol patients were older (median age, 49.2 (19.2) vs. 40.5 (16.8) years; p = 0.02), with higher Injury Severity Scores (42 (15.9) vs. 32.1 [11.3]; p = 0.001), and IMPACT-TBI predicted 6-month mortality (34.5% [23-46] vs. 25% [13-38]; p = 0.02), but had similar APACHE-II scores, and mean and maximum ICPs over the first 96 h. The unadjusted hazard ratio for in-hospital mortality in patients receiving only mannitol was 3.35 (95% confidence interval [CI], 1.60-7.03; p = 0.001). After adjustment for key mortality predictors, the hazard ratio for in-hospital mortality in patients receiving only mannitol was 2.64 (95% CI, 0.96-7.30; p = 0.06). The choice of early osmotherapy in severe TBI patients may affect survival, or simply reflect clinician beliefs about their different roles, and warrants controlled investigation.

Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial.

BACKGROUND: Cardiopulmonary bypass (CPB) is often associated with degrees of complex inflammatory response mediated by various cytokines. This response can, in severe cases, lead to systemic hypotension and organ dysfunction. Cytokine removal might therefore improve outcomes of patients undergoing cardiac surgery. CytoSorb® (Cytosorbents, NJ, USA) is a recent device designed to remove cytokine from the blood using haemoadsorption (HA). This trial aims to evaluate the potential of CytoSorb® to decrease peri-operative cytokine levels in cardiac surgery. METHODS: We have conducted a single-centre pilot randomized controlled trial in 30 patients undergoing elective cardiac surgery and deemed at risk of complications. Patients were randomly allocated to either standard of care (n = 15) or CytoSorb® HA (n = 15) during cardiopulmonary bypass (CPB). Our primary outcome was the difference between the two groups in cytokines levels (IL-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, IFN-γ, MCP-1) measured at anaesthesia induction, at the end of CPB, as well as 6 and 24 h post-CPB initiation. In a consecutive subgroup of patients (10 in HA group, 11 in control group), we performed cross-adsorber as well as serial measurements of coagulation factors' activity (antithrombin, von Willebrand factor, factor II, V, VIII, IX, XI, and XII). RESULTS: Both groups were similar in terms of baseline and peri-operative characteristics. CytoSorb® HA during CPB was not associated with an increased incidence of adverse event. The procedure did not result in significant coagulation factors' adsorption but only some signs of coagulation activation. However, the intervention was associated neither with a decrease in pro- or anti-inflammatory cytokine levels nor with any improvement in relevant clinical outcomes. CONCLUSIONS: CytoSorb® HA during CPB was not associated with a decrease in pro- or anti-inflammatory cytokines nor with an improvement in relevant clinical outcomes. The procedure was feasible and safe. Further studies should evaluate the efficacy of CytoSorb® HA in other clinical contexts. TRIAL REGISTRATION: ClinicalTrials.gov NCT02775123 . Registered 17 May 2016.

Continuous renal replacement therapy: understanding circuit hemodynamics to improve therapy adequacy.

PURPOSE OF REVIEW: The utilization of continuous renal replacement therapy (CRRT) increases throughout the world. Technological improvements have made its administration easier and safer. However, CRRT remains associated with numerous pitfalls and issues. RECENT FINDINGS: Even if new-generation CRRT devices have built-in safety features, understanding basic concepts remains of primary importance. SUMMARY: CRRT circuits' maximum recommended lifespan (72 h) can often not be achieved. Such early artificial kidney failures are typically related to two processes: circuit clotting and membrane clogging. Although these processes are to some degree inevitable, they are facilitated by poor therapy management. Indeed, the majority of device-triggered alarms are associated with blood pump interruption, which through blood stasis, enhance clotting and clogging. If the underlying issue is not adequately managed, further alarms will rapidly lead to prolonged stasis and complete circuit clotting or clogging making its replacement mandatory. Hence, rapid recognition of issues triggering alarms is of paramount importance. Because most alarms are related to circuit's hemodynamics, a thorough understanding of these concepts is mandatory for the staff in charge of delivering the therapy.This review describes CRRT circuits, measured and calculated pressures and the way their knowledge might improve therapy adequacy.

Renal Replacement Therapy Modality in the ICU and Renal Recovery at Hospital Discharge.

OBJECTIVES: Acute kidney injury requiring renal replacement therapy is a major concern in ICUs. Initial renal replacement therapy modality, continuous renal replacement therapy or intermittent hemodialysis, may impact renal recovery. The aim of this study was to assess the influence of initial renal replacement therapy modality on renal recovery at hospital discharge. DESIGN: Retrospective cohort study of all ICU stays from January 1, 2010, to December 31, 2013, with a "renal replacement therapy for acute kidney injury" code using the French hospital discharge database. SETTING: Two hundred ninety-one ICUs in France. PATIENTS: A total of 1,031,120 stays: 58,635 with renal replacement therapy for acute kidney injury and 25,750 included in the main analysis. INTERVENTIONS: None. MEASUREMENTS MAIN RESULTS: PPatients alive at hospital discharge were grouped according to initial modality (continuous renal replacement therapy or intermittent hemodialysis) and included in the main analysis to identify predictors of renal recovery. Renal recovery was defined as greater than 3 days without renal replacement therapy before hospital discharge. The main analysis was a hierarchical logistic regression analysis including patient demographics, comorbidities, and severity variables, as well as center characteristics. Three sensitivity analyses were performed. Overall mortality was 56.1%, and overall renal recovery was 86.2%. Intermittent hemodialysis was associated with a lower likelihood of recovery at hospital discharge; odds ratio, 0.910 (95% CI, 0.834-0.992) p value equals to 0.0327. Results were consistent across all sensitivity analyses with odds/hazards ratios ranging from 0.883 to 0.958. CONCLUSIONS: In this large retrospective study, intermittent hemodialysis as an initial modality was associated with lower renal recovery at hospital discharge among patients with acute kidney injury, although the difference seems somewhat clinically limited.