Evaluation of Clinical and Machine Data of Critically Ill Adult COVID Patients with Acute Kidney Injury Exposed to Enhanced Hemoadsorption during CRRT.

INTRODUCTION: The FDA authorized the emergency use of enhanced hemoadsorption with oXiris in critically ill adult COVID patients with respiratory failure or severe disease to reduce inflammation. In this study, we evaluated critically ill adult COVID patients with acute kidney injury (AKI) who were exposed versus not exposed to enhanced hemoadsorption with oXiris during continuous renal replacement therapy (CRRT). METHODS: Retrospective cohort study of critically ill adult COVID patients with AKI requiring CRRT. Exposure to oXiris was defined as receiving oXiris for >12 cumulative hours and more than one-third of the time within the first 72 h of CRRT. Study outcomes included filter-specific performance metrics and clinical outcomes such as ventilator requirement, mortality, and dialysis dependence. Inverse probability treatment weighting was used to balance potential confounders in weighted regression models. RESULTS: 14,043 h of CRRT corresponding to 85 critically ill adult patients were analyzed. Among these, 2,736 h corresponded to oXiris exposure (n = 25 patients) and 11,307 h to a standard CRRT filter (n = 60 patients). Transmembrane pressures (TMPs) increased rapidly and were overall higher with oXiris versus standard filter, but filter life (median of 36.3 vs. 33.1 h, p = 0.913, respectively) and filter/clotting alarms remained similar in both groups. In adjusted models, oXiris exposure was not independently associated with the composite of hospital mortality and dialysis dependence at discharge (OR 2.13, 95% CI: 0.98-4.82, p = 0.06), but it was associated with fewer ventilator (ß = -15.02, 95% CI: -29.23 to -0.82, p = 0.04) and intensive care unit days (ß = -14.74, 95% CI: -28.54 to -0.95, p = 0.04) in survivors. DISCUSSION/CONCLUSION: In critically ill adult COVID patients with AKI requiring CRRT, oXiris filters exhibited higher levels of TMP when compared to a standard CRRT filter, but no differences in filter life and filter/clotting alarm profiles were observed. The use of oXiris was not associated with improvement in clinical outcomes such as hospital mortality or dialysis dependence at discharge.

Acute kidney injury in neurocritical care.

Approximately 20% of patients with acute brain injury (ABI) also experience acute kidney injury (AKI), which worsens their outcomes. The metabolic and inflammatory changes associated with AKI likely contribute to prolonged brain injury and edema. As a result, recognizing its presence is important for effectively managing ABI and its sequelae. This review discusses the occurrence and effects of AKI in critically ill adults with neurological conditions, outlines potential mechanisms connecting AKI and ABI progression, and highlights AKI management principles. Tailored approaches include optimizing blood pressure, managing intracranial pressure, adjusting medication dosages, and assessing the type of administered fluids. Preventive measures include avoiding nephrotoxic drugs, improving hemodynamic and fluid balance, and addressing coexisting AKI syndromes. ABI patients undergoing renal replacement therapy (RRT) are more susceptible to neurological complications. RRT can negatively impact cerebral blood flow, intracranial pressure, and brain tissue oxygenation, with effects tied to specific RRT methods. Continuous RRT is favored for better hemodynamic stability and lower risk of dialysis disequilibrium syndrome. Potential RRT modifications for ABI patients include adjusted dialysate and blood flow rates, osmotherapy, and alternate anticoagulation methods. Future research should explore whether these strategies enhance outcomes and if using novel AKI biomarkers can mitigate AKI-related complications in ABI patients.

Timing of Renal Replacement Therapy for Acute Kidney Injury.

Acute kidney injury (AKI) is common in critically ill patients and associated with increased morbidity and mortality. With the increased use of renal replacement therapy (RRT) for severe AKI, the optimal time for initiation of RRT has become one of the most probed and debated topic in the field of nephrology and critical care. There appears to be an increased trend toward earlier initiation of RRT to avoid life-threatening complications associated with AKI. Despite the presence of a plethora of studies in this field, the lack of uniformity in study design, patient population types, definition of early and late initiation, modality of RRT, and results, the optimal time for starting RRT in AKI still remains unknown. The beneficial effects reported in observational studies have not been supported by clinical trials. Recently, 2 of the largest randomized control trials evaluating the timing of RRT in critically ill patients with AKI showed differing results. We provide an in-depth review of the available data on the timing of dialysis in patients with AKI.

KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury.

In response to the recently released 2012 KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for acute kidney injury (AKI), the National Kidney Foundation organized a group of US experts in adult and pediatric AKI and critical care nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The first portion of the KDIGO guideline attempts to harmonize earlier consensus definitions and staging criteria for AKI. While the expert panel thought that the KDIGO definition and staging criteria are appropriate for defining the epidemiology of AKI and in the design of clinical trials, the panel concluded that there is insufficient evidence to support their widespread application to clinical care in the United States. The panel generally concurred with the remainder of the KDIGO guidelines that are focused on the prevention and pharmacologic and dialytic management of AKI, although noting the dearth of clinical trial evidence to provide strong evidence-based recommendations and the continued absence of effective therapies beyond hemodynamic optimization and avoidance of nephrotoxins for the prevention and treatment of AKI.

The effect of the selective cytopheretic device on acute kidney injury outcomes in the intensive care unit: a multicenter pilot study.

Acute kidney injury (AKI) is characterized by deterioration in kidney function resulting in multisystem abnormalities. Much of the morbidity and mortality associated with AKI result from a systemic inflammatory response syndrome (SIRS). This study described herein is a prospective, single-arm, multicenter US study designed to evaluate the safety and efficacy of the Selective Cytopheretic Device (SCD) treatment on AKI requiring continuous renal replacement therapy (CRRT) in the ICU. The study enrolled 35 subjects. The mean age was 56.3±15. With regard to race, 71.4% of the subjects were Caucasian, 22.9% were Black, and 5.7% were Hispanic. Average SOFA score was 11.3±3.6. Death from any cause at Day 60 was 31.4%. Renal recovery, defined as dialysis independence, was observed in all of the surviving subjects at Day 60. The results of this pilot study indicate the potential for a substantial improvement in patient outcomes over standard of care therapy, which is associated with a greater than 50% 60-day mortality in the literature. The SCD warrants further study in scientifically sound, pivotal trial to demonstrate reasonable assurance of safety and effectiveness.

Debate: Intermittent Hemodialysis versus Continuous Kidney Replacement Therapy in the Critically Ill Patient: The Argument for CKRT.

Continuous kidney replacement therapy (CKRT) is well entrenched as one of the dominant KRT modalities in modern critical care practice. Since its introduction four decades ago, there have been considerable innovations in CKRT machines that have improved precision, safety, and simplicity. CKRT is the preferred KRT modality for critically ill patients with hemodynamic instability. Early physical therapy and rehabilitation can be feasibly and safely provided to patients connected to CKRT, thus obviating concerns about immobility. Although randomized clinical trials have not shown a mortality difference when comparing CKRT and intermittent hemodialysis, CKRT allows precision delivery of solute and fluid removal that can be readily adjusted in the face of dynamic circumstances. Accumulated evidence from observational studies, although susceptible to bias, has shown that CKRT, when compared with intermittent hemodialysis, is associated with better short- and long-term kidney recovery and KRT independence. Critical care medicine encompasses a wide range of sick patients, and no single KRT modality is likely to ideally suit every patient in every context and for every condition. The provision of KRT represents a spectrum of modalities to which patients can flexibly transition in response to their evolving condition. As a vital tool for organ support in the intensive care unit, CKRT enables the personalization of KRT to meet the clinical demands of patients during the most severe phases of their illness.

Critical care nephrology: management of acid-base disorders with CRRT.

Normal acid-base homeostasis is severely challenged in the intensive care setting. In this review, we address acid-base disturbances, with a special focus on the use of continuous (rather than intermittent) extracorporeal technologies in critical ill patients with acute kidney injury. We consider hypercapnic acidosis and lactic acidosis as examples in which continuous modalities may have different roles and indications than the traditional intermittent approaches to renal replacement therapy. Hypercapnic acidosis develops as a consequence of alveolar hypoventilation. In this condition, correction of pH above 7.2 is not currently recommended, and may even abrogate the beneficial effects of hypercapnic acidosis on overall outcomes. Extracorporeal technologies support lung protection while maintaining overall patient homeostasis. Similarly, in lactic acidosis, current evidence does not support bicarbonate infusions to correct acidosis. The management of lactic acidosis should correct the underlying causative disturbances. Most often, lactic acidosis is a biomarker denoting unfavorable outcomes, rather than an intrinsic pathogenetic mechanism. Extracorporeal procedures may assist in the removal of pathogenic drugs or toxins, as well as partially correcting acidemia. Whether or not these approaches will permit normalization of systemic pH, and the impact of these approaches on patient outcomes, needs to be addressed with prospective controlled trials.

Solute clearance in CRRT: prescribed dose versus actual delivered dose.

BACKGROUND: Substantial efforts have been made toward defining the dose threshold of continuous renal replacement therapy (CRRT) associated with improved survival in critically ill patients with acute kidney injury. Published studies have used prescribed effluent rates, expressed as total effluent volume (TEV) per weight and unit time (mL/kg/h), as a surrogate for dose. The purpose of this study was to compare differences in CRRT dose based on prescribed effluent rate, measured TEV and direct measurement of urea and creatinine clearance. METHODS: We analyzed data that had been prospectively collected on 200 patients enrolled in a randomized trial comparing survival with a prescribed effluent rate of 20 mL/kg/h (standard dose) to 35 mL/kg/h (high dose) using pre-dilution continuous venovenous hemodiafiltration (CVVHDF). Filters were changed every 72 h. Blood urea nitrogen (BUN), serum creatinine (SCr), effluent urea nitrogen (EUN) and effluent creatinine (ECr) were collected daily. Actual delivered dose was calculated as: (EUN/BUN)*TEV for urea and (ECr/SCr)*TEV for creatinine. Data were available for 165 patients. RESULTS: In both groups, prescribed dose differed significantly from the measured TEV dose (P < 0.001). In the standard dose group, there was no difference between the measured TEV dose and actual delivered urea and creatinine clearances. However, in the high-dose group, measured TEV dose differed significantly from delivered urea clearance by 7.1% (P < 0.001) and creatinine clearance by 13.9% (P < 0.001). CONCLUSIONS: Dose based on prescribed effluent rate or measured TEV is a poor substitute for actual CVVHDF creatinine and urea clearance.

Fluid Responsiveness in the Critically Ill Patient.

Accurate assessment of intravascular volume status in critically ill patients remains a very challenging task. Recent data have shown adverse outcomes in critically ill patients with either inadequate or overaggressive fluid therapy. Understanding the tools and techniques available for accurate volume assessment is imperative. This article discusses the concept of fluid responsiveness and reviews methods for assessing fluid responsiveness in critically ill patients.

How To Prescribe And Troubleshoot Continuous Renal Replacement Therapy: A Case-Based Review.

Continuous RRT (CRRT) is the preferred dialysis modality for solute management, acid-base stability, and volume control in patients who are critically ill with AKI in the intensive care unit (ICU). CRRT offers multiple advantages over conventional hemodialysis in the critically ill population, such as greater hemodynamic stability, better fluid management, greater solute control, lower bleeding risk, and a more continuous (physiologic) approach of kidney support. Despite its frequent use, several aspects of CRRT delivery are still not fully standardized, or do not have solid evidence-based foundations. In this study, we provide a case-based review and recommendations of common scenarios and interventions encountered during the provision of CRRT to patients who are critically ill. Specific focus is on initial prescription, CRRT dosing, and adjustments related to severe hyponatremia management, concomitant extracorporeal membrane oxygenation support, dialysis catheter placement, use of regional citrate anticoagulation, and antibiotic dosing. This case-driven simulation is made as the clinical status of the patient evolves, and is on the basis of step-wise decisions made during the care of this patient, according to the specific patient's needs and the logistics available at the corresponding institution.

Anticoagulation for continuous renal replacement therapy.

Continuous renal replacement therapy (CRRT) has emerged as the preferred dialysis modality for critically ill patients with acute kidney injury, particularly those with hemodynamic instability. Anticoagulation is necessary for effective delivery of CRRT, but this requirement can also present challenges, as many critically ill patients with sepsis and inflammation already have a higher risk of bleeding as well as clotting. Without anticoagulation, CRRT filter and circuit survival are diminished, and therapy becomes less helpful. Heparins are presently the most commonly used anticoagulants worldwide for CRRT. They are widely available and can be easily monitored, but disadvantages include risks of hemorrhage, heparin resistance, and heparin-induced thrombocytopenia (HIT). Because of the potential side effects of heparin, alternative methods of anticoagulation have been investigated, including regional heparin/protamine, low molecular weight heparins, heparinoids, thrombin antagonists (hirudin and argatroban), regional citrate, and platelet inhibiting agents (prostacyclin and nafamostat). Each of these techniques has unique advantages and disadvantages, and anticoagulation for CRRT should be adapted to the patient's characteristics and institution's experience. Of the alternative methods, citrate anticoagulation is gaining wider acceptance with the development of simplified and safer protocols.

Standard versus high-dose CVVHDF for ICU-related acute renal failure.

The effect of dosage of continuous venovenous hemodiafiltration (CVVHDF) on survival in patients with acute renal failure (ARF) is unknown. In this study, 200 critically ill patients with ARF were randomly assigned to receive CVVHDF with prefilter replacement fluid at an effluent rate of either 35 ml/kg per h (high dosage) or 20 ml/kg per h (standard dosage). The primary study outcome, survival to the earlier of either intensive care unit discharge or 30 d, was 49% in the high-dosage arm and 56% in the standard-dosage arm (odds ratio 0.75; 95% confidence interval 0.43 to 1.32; P = 0.32). Among hospital survivors, 69% of those in the high-dosage arm recovered renal function compared with 80% of those in the standard-dosage arm (P = 0.29); therefore, a difference in patient survival or renal recovery was not detected between patients receiving high-dosage or standard-dosage CVVHDF.

Efficacy and safety of renal tubule cell therapy for acute renal failure.

The mortality rate for patients with acute renal failure (ARF) remains unacceptably high. Although dialysis removes waste products and corrects fluid imbalance, it does not perform the absorptive, metabolic, endocrine, and immunologic functions of normal renal tubule cells. The renal tubule assist device (RAD) is composed of a conventional hemofilter lined by monolayers of renal cells. For testing whether short-term (up to 72 h) treatment with the RAD would improve survival in patients with ARF compared with conventional continuous renal replacement therapy (CRRT), a Phase II, multicenter, randomized, controlled, open-label trial involving 58 patients who had ARF and required CRRT was performed. Forty patients received continuous venovenous hemofiltration + RAD, and 18 received CRRT alone. The primary efficacy end point was all-cause mortality at 28 d; additional end points included all-cause mortality at 90 and 180 d, time to recovery of renal function, time to intensive care unit and hospital discharge, and safety. At day 28, the mortality rate was 33% in the RAD group and 61% in the CRRT group. Kaplan-Meier analysis revealed that survival through day 180 was significantly improved in the RAD group, and Cox proportional hazards models suggested that the risk for death was approximately 50% of that observed in the CRRT-alone group. RAD therapy was also associated with more rapid recovery of kidney function, was well tolerated, and had the expected adverse event profile for critically ill patients with ARF.

The epidemiology of severe acute kidney injury: from BEST to PICARD, in acute kidney injury: new concepts.

Various definitions of acute kidney injury (AKI) exist, making comparisons among studies difficult. Despite this, significant changes have occurred in the epidemiology of AKI during the last decade. Recent studies, including PICARD and BEST, have examined the epidemiology of ICU-related AKI in the USA and worldwide, respectively, and found that AKI remains a major cause of morbidity and mortality. The incidence of AKI has increased, most likely due to a trend toward older, more severely and chronically ill patients admitted to the hospital. Sepsis and multi-organ system failure continue to be strongly associated with AKI, as well as pre-morbid chronic kidney disease. The proportion of patients with AKI requiring dialysis is high. The mortality of ICU-related AKI, although still very elevated, may be decreasing. Understanding these changes, in the context of standardized definitions, will be essential for the design of successful interventional studies.

A Monte Carlo Simulation Approach for Beta-Lactam Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy.

Cefepime, ceftazidime, and piperacillin/tazobactam are commonly used beta-lactam antibiotics in the critical care setting. For critically ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic data are available to inform clinicians on the dosing of these agents. Monte Carlo simulations (MCS) can be used to guide drug dosing when pharmacokinetic trials are not feasible. For each antibiotic, MCS using previously published pharmacokinetic data derived from critically ill patients was used to evaluate multiple dosing regimens in 4 different prolonged intermittent renal replacement therapy effluent rates and prolonged intermittent renal replacement therapy duration combinations (4 L/h × 10 hours or 5 L/h × 8 hours in hemodialysis and hemofiltration modes). Antibiotic regimens were also modeled depending on whether drugs were administered during or well before prolonged intermittent renal replacement therapy therapy commenced. The probability of target attainment (PTA) was calculated using each antibiotic's pharmacodynamic target during the first 48 hours of therapy. Optimal doses were defined as the smallest daily dose achieving ≥90% probability of target attainment in all prolonged intermittent renal replacement therapy effluent and duration combinations. Cefepime 1 g every 6 hours following a 2 g loading dose, ceftazidime 2 g every 12 hours, and piperacillin/tazobactam 4.5 g every 6 hours attained the desired pharmacodynamic target in ≥90% of modeled prolonged intermittent renal replacement therapy patients. Alternatively, if an every 6-hours cefepime regimen is not desired, the cefepime 2 g pre-prolonged intermittent renal replacement therapy and 3 g post-prolonged intermittent renal replacement therapy regimen also met targets. For ceftazidime, 1 g every 6 hours or 3 g continuous infusion following a 2 g loading dose also met targets. These recommended doses provide simple regimens that are likely to achieve the pharmacodynamics target while yielding the least overall drug exposure, which should result in lower toxicity rates. These findings should be validated in the clinical setting.

Current state of the art for renal replacement therapy in critically ill patients with acute kidney injury.

Acute kidney injury (AKI) is associated with incremental risk for death and chronic kidney disease and represents a mounting clinical challenge for healthcare professionals. Renal replacement therapy (RRT) use in ICU settings is rising, likely in response to similar trends in AKI, taken together with an ageing population burdened by high prevalence of multi-morbidity and high illness acuity. Numerous features of RRT prescription and delivery are not standardized, nor are they supported from high-quality evidence derived from randomized trials. Despite the publication of rigorous clinical practice guidelines focused on RRT for AKI that are intended to optimize the quality and reliability of RRT in ICU settings, practice patterns and outcomes continue to show significant variability. In this concise review, we aim to summarize new knowledge and recent advances for the provision of RRT for critically ill patients with AKI.

Pharmacokinetics and Pharmacodynamics of Extended Infusion Versus Short Infusion Piperacillin-Tazobactam in Critically Ill Patients Undergoing CRRT.

BACKGROUND AND OBJECTIVES: Infection is the most common cause of death in severe AKI, but many patients receiving continuous RRT do not reach target antibiotic concentrations in plasma. Extended infusion of ß-lactams is associated with improved target attainment in critically ill patients; thus, we hypothesized that extended infusion piperacillin-tazobactam would improve piperacillin target attainment compared with short infusion in patients receiving continuous RRT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted an institutional review board-approved observational cohort study of piperacillin-tazobactam pharmacokinetics and pharmacodynamics in critically ill patients receiving continuous venovenous hemodialysis and hemodiafiltration at three tertiary care hospitals between 2007 and 2015. Antibiotic concentrations in blood and/or dialysate samples were measured by liquid chromatography, and one- and two-compartment pharmacokinetic models were fitted to the data using nonlinear mixed effects regression. Target attainment for piperacillin was defined as achieving four times the minimum inhibitory concentration of 16 µg/ml for >50% of the dosing cycle. The probabilities of target attainment for a range of doses, frequencies, and infusion durations were estimated using a Monte Carlo simulation method. Target attainment was also examined as a function of patient weight and continuous RRT effluent rate. RESULTS: Sixty-eight participants had data for analysis. Regardless of infusion duration, 6 g/d piperacillin was associated with ≤45% target attainment, whereas 12 g/d was associated with ≥95% target attainment. For 8 and 9 g/d, target attainment ranged between 68% and 85%. The probability of target attainment was lower at higher effluent rates and patient weights. For all doses, frequencies, patient weights, and continuous RRT effluent rates, extended infusion was associated with higher probability of target attainment compared with short infusion. CONCLUSIONS: Extended infusions of piperacillin-tazobactam are associated with greater probability of target attainment in patients receiving continuous RRT.

Assessing continuous renal replacement therapy as a rescue strategy in cardiorenal syndrome 1.

BACKGROUND: Patients with acute decompensated heart failure (ADHF) and cardiorenal syndrome (CRS) 1 have poor outcomes. Ultrafiltration (UF) is used to mechanically remove salt and water in ADHF patients with diuretic resistance. However, little is known about the outcomes of ADHF patients on inotropes and/or vasopressors who require continuous renal replacement therapy (CRRT) for both UF and solute clearance in severe acute kidney injury. METHODS: We retrospectively analyzed 37 consecutive critically ill patients who were admitted for ADHF from 2005-13 and were on inotropes and/or vasopressors at the time of CRRT initiation. The primary outcome was in-hospital mortality. RESULTS: In-hospital mortality rate was 62%. Median survival was 15.5 days after CRRT initiation, and 10 months following hospital discharge. When comparing renal and cardiovascular variables for survivors and non-survivors at baseline, admission and CRRT initiation, survivors were less likely to need vasopressors. After controlling for multiple predictors, vasopressor use remained associated with time to death (HR 9.9; 95% CI 2.3-43.3; P = 0.002). Patients with isolated right ventricular dysfunction had an in-hospital mortality of 45% compared with 69% in those with left ventricular dysfunction (P = 0.27). Age of >70 years was associated with 100% in-hospital mortality. CONCLUSIONS: Rescue therapy using CRRT in refractory CRS1 was associated with high in-hospital mortality, especially when vasopressors were used and when patient age exceeded 70 years. Additionally, survivors had a poor long-term prognosis.