Dinna N. Cruz

Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock: The EUPHAS Randomized Controlled Trial

CONTEXT Polymyxin B fiber column is a medical device designed to reduce blood endotoxin levels in sepsis. Gram-negative-induced abdominal sepsis is likely associated with high circulating endotoxin. Reducing circulating endotoxin levels with polymyxin B hemoperfusion could potentially improve patient clinical outcomes. OBJECTIVE To determine whether polymyxin B hemoperfusion added to conventional medical therapy improves clinical outcomes (mean arterial pressure [MAP], vasopressor requirement, oxygenation, organ dysfunction) and mortality compared with conventional therapy alone. DESIGN, SETTING, AND PATIENTS A prospective, multicenter, randomized controlled trial (Early Use of Polymyxin B Hemoperfusion in Abdominal Sepsis [EUPHAS]) conducted at 10 Italian tertiary care intensive care units between December 2004 and December 2007. Sixty-four patients were enrolled with severe sepsis or septic shock who underwent emergency surgery for intra-abdominal infection. INTERVENTION Patients were randomized to either conventional therapy (n=30) or conventional therapy plus 2 sessions of polymyxin B hemoperfusion (n=34). MAIN OUTCOME MEASURES Primary outcome was change in MAP and vasopressor requirement, and secondary outcomes were PaO(2)/FIO(2) (fraction of inspired oxygen) ratio, change in organ dysfunction measured using Sequential Organ Failure Assessment (SOFA) scores, and 28-day mortality. RESULTS MAP increased (76 to 84 mm Hg; P = .001) and vasopressor requirement decreased (inotropic score, 29.9 to 6.8; P < .001) at 72 hours in the polymyxin B group but not in the conventional therapy group (MAP, 74 to 77 mm Hg; P = .37; inotropic score, 28.6 to 22.4; P = .14). The PaO(2)/FIO(2) ratio increased slightly (235 to 264; P = .049) in the polymyxin B group but not in the conventional therapy group (217 to 228; P = .79). SOFA scores improved in the polymyxin B group but not in the conventional therapy group (change in SOFA, -3.4 vs -0.1; P < .001), and 28-day mortality was 32% (11/34 patients) in the polymyxin B group and 53% (16/30 patients) in the conventional therapy group (unadjusted hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.20-0.94; adjusted HR, 0.36; 95% CI, 0.16-0.80). CONCLUSION In this preliminary study, polymyxin B hemoperfusion added to conventional therapy significantly improved hemodynamics and organ dysfunction and reduced 28-day mortality in a targeted population with severe sepsis and/or septic shock from intra-abdominal gram-negative infections. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00629382.

The Outcome of Neutrophil Gelatinase-Associated Lipocalin-Positive Subclinical Acute Kidney Injury: A Multicenter Pooled Analysis of Prospective Studies

OBJECTIVES The aim of this study was to test the hypothesis that, without diagnostic changes in serum creatinine, increased neutrophil gelatinase-associated lipocalin (NGAL) levels identify patients with subclinical acute kidney injury (AKI) and therefore worse prognosis. BACKGROUND Neutrophil gelatinase-associated lipocalin detects subclinical AKI hours to days before increases in serum creatinine indicate manifest loss of renal function. METHODS We analyzed pooled data from 2,322 critically ill patients with predominantly cardiorenal syndrome from 10 prospective observational studies of NGAL. We used the terms NGAL(-) or NGAL(+) according to study-specific NGAL cutoff for optimal AKI prediction and the terms sCREA(-) or sCREA(+) according to consensus diagnostic increases in serum creatinine defining AKI. A priori-defined outcomes included need for renal replacement therapy (primary endpoint), hospital mortality, their combination, and duration of stay in intensive care and in-hospital. RESULTS Of study patients, 1,296 (55.8%) were NGAL(-)/sCREA(-), 445 (19.2%) were NGAL(+)/sCREA(-), 107 (4.6%) were NGAL(-)/sCREA(+), and 474 (20.4%) were NGAL(+)/sCREA(+). According to the 4 study groups, there was a stepwise increase in subsequent renal replacement therapy initiation-NGAL(-)/sCREA(-): 0.0015% versus NGAL(+)/sCREA(-): 2.5% (odds ratio: 16.4, 95% confidence interval: 3.6 to 76.9, p < 0.001), NGAL(-)/sCREA(+): 7.5%, and NGAL(+)/sCREA(+): 8.0%, respectively, hospital mortality (4.8%, 12.4%, 8.4%, 14.7%, respectively) and their combination (4-group comparisons: all p < 0.001). There was a similar and consistent progressive increase in median number of intensive care and in-hospital days with increasing biomarker positivity: NGAL(-)/sCREA(-): 4.2 and 8.8 days; NGAL(+)/sCREA(-): 7.1 and 17.0 days; NGAL(-)/sCREA(+): 6.5 and 17.8 days; NGAL(+)/sCREA(+): 9.0 and 21.9 days; 4-group comparisons: p = 0.003 and p = 0.040, respectively. Urine and plasma NGAL indicated a similar outcome pattern. CONCLUSIONS In the absence of diagnostic increases in serum creatinine, NGAL detects patients with likely subclinical AKI who have an increased risk of adverse outcomes. The concept and definition of AKI might need re-assessment.

Acute kidney injury: an increasing global concern

Despite an increasing incidence of acute kidney injury in both high-income and low-income countries and growing insight into the causes and mechanisms of disease, few preventive and therapeutic options exist. Even small acute changes in kidney function can result in short-term and long-term complications, including chronic kidney disease, end-stage renal disease, and death. Presence of more than one comorbidity results in high severity of illness scores in all medical settings. Development or progression of chronic kidney disease after one or more episode of acute kidney injury could have striking socioeconomic and public health outcomes for all countries. Concerted international action encompassing many medical disciplines is needed to aid early recognition and management of acute kidney injury.

World Incidence of AKI: A Meta-Analysis

BACKGROUND AND OBJECTIVES The burden of AKI around the globe has not been systematically examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A systematic review (2004-2012) of large cohort studies was conducted to estimate the world incidence of AKI and its stages of severity and associated mortality, and to describe geographic variations according to countries, regions, and their economies. AKI definitions were reclassified according to the Kidney Disease Improving Global Outcomes (KDIGO) staging system. Random-effects model meta-analyses and meta-regressions were used to generate summary estimates and explore sources of heterogeneity. RESULTS There were 312 studies identified (n=49,147,878) , primarily in hospital settings. Most studies originated from North America, Northern Europe, and Eastern Asia, from high-income countries, and from nations that spent ≥5% of the gross domestic product on total health expenditure. Among the 154 studies (n=3,585,911) that adopted a KDIGO-equivalent AKI definition, the pooled incidence rates of AKI were 21.6% in adults (95% confidence interval [95% CI], 19.3 to 24.1) and 33.7% in children (95% CI, 26.9 to 41.3). The pooled AKI-associated mortality rates were 23.9% in adults (95% CI, 22.1 to 25.7) and 13.8% in children (95% CI, 8.8 to 21.0). The AKI-associated mortality rate declined over time, and was inversely related to income of countries and percentage of gross domestic product spent on total health expenditure. CONCLUSIONS Using the KDIGO definition, 1 in 5 adults and 1 in 3 children worldwide experience AKI during a hospital episode of care. This analysis provides a platform to raise awareness of AKI with the public, government officials, and health care professionals.

Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review

IntroductionSevere sepsis and septic shock are common problems in the intensive care unit and carry a high mortality. Endotoxin, one of the principal components on the outer membrane of gram-negative bacteria, is considered important to their pathogenesis. Polymyxin B bound and immobilized to polystyrene fibers (PMX-F) is a medical device that aims to remove circulating endotoxin by adsorption, theoretically preventing the progression of the biological cascade of sepsis. We performed a systematic review to describe the effect in septic patients of direct hemoperfusion with PMX-F on outcomes of blood pressure, use of vasoactive drugs, oxygenation, and mortality reported in published studies.MethodsWe searched PubMed, the Cochrane Collaboration Database, and bibliographies of retrieved articles and consulted with experts to identify relevant studies. Prospective and retrospective observational studies, pre- and post-intervention design, and randomized controlled trials were included. Three authors reviewed all citations. We identified a total of 28 publications – 9 randomized controlled trials, 7 non-randomized parallel studies, and 12 pre-post design studies – that reported at least one of the specified outcome measures (pooled sample size, 1,425 patients: 978 PMX-F and 447 conventional medical therapy).ResultsOverall, mean arterial pressure (MAP) increased by 19 mm Hg (95% confidence interval [CI], 15 to 22 mm Hg; p < 0.001), representing a 26% mean increase in MAP (range, 14% to 42%), whereas dopamine/dobutamine dose decreased by 1.8 μg/kg per minute (95% CI, 0.4 to 3.3 μg/kg per minute; p = 0.01) after PMX-F. There was significant intertrial heterogeneity for these outcomes (p < 0.001), which became non-significant when analysis was stratified for baseline MAP. The mean arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio increased by 32 units (95% CI, 23 to 41 units; p < 0.001). PMX-F therapy was associated with significantly lower mortality risk (risk ratio, 0.53; 95% CI, 0.43 to 0.65). The trials assessed had suboptimal method quality.ConclusionBased on this critical review of the published literature, direct hemoperfusion with PMX-F appears to have favorable effects on MAP, dopamine use, PaO2/FiO2 ratio, and mortality. However, publication bias and lack of blinding need to be considered. These findings support the need for further rigorous study of this therapy.

North East Italian Prospective Hospital Renal Outcome Survey on Acute Kidney Injury (NEiPHROS-AKI): Targeting the Problem with the RIFLE Criteria

Acute kidney injury (AKI) in the intensive care unit (ICU) is associated with an enhanced mortality. The Acute Dialysis Quality Initiative group has proposed the RIFLE (Risk-Injury-Failure-Loss-ESRD) classification to standardize the approach to AKI. This study was performed to estimate the AKI incidence in ICU patients in northeastern Italy and describe clinical characteristics and outcomes of patients with AKI on the basis of their RIFLE class. A prospective multicenter observational study was performed of patients who fulfilled AKI criteria in 19 ICU in northeastern Italy. Data were analyzed using multivariate logistic regression and survival curve analysis. Of 2164 ICU patients who were admitted during the study period, 234 (10.8%; 95% confidence interval 9.5 to 12.1%) developed AKI; 19% were classified as risk (R), 35% as injury (I), and 46% as failure (F). Preexisting kidney disease was present in 36.8%. The most common causes of AKI were prerenal causes (38.9%) and sepsis (25.6%). At diagnosis of AKI, median serum creatinine and urine output were 2.0 mg/dl and 1100 ml/d, respectively. ICU mortality was 49.5% in class F, 29.3% in I, and 20% in R. Independent risk factors for mortality included RIFLE class, sepsis, and need for renal replacement therapy, whereas a postsurgical cause of AKI, exposure to nephrotoxins, higher serum creatinine, and urine output were associated with lower mortality risk. In this study, AKI incidence in the ICU was between 9 and 12%, with 3.3% of ICU patients requiring renal replacement therapy. Sepsis was a significant contributing factor. Overall mortality was between 30 and 42%, and was highest among those in RIFLE class F.

International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology

Executive summary Acute kidney injury (AKI) is a major contributor to poor patient outcomes. AKI occurs in about 13·3 million people per year, 85% of whom live in the developing world, and, although no direct link between AKI and death has yet been shown, AKI is thought to contribute to about 1·7 million deaths every year. The course of AKI varies with the setting in which it occurs, and the severity and duration of AKI aff ects outcomes such as dialysis requirement, renal functional recovery, and survival. Recognition is increasing for the eff ect of AKI on patients, and the resulting societal burden from its longterm eff ects, including development of chronic kidney disease and end-stage renal disease needing dialysis or trans plantation. Few systematic eff orts to manage (prevent, diagnose, and treat) AKI have been put in place and few resources have been allocated to inform health-care professionals and the public of the importance of AKI as a preventable and treatable disease. Several factors have contributed to the paucity of information. Most importantly, there have been few population-level epidemiological studies in several regions of the world. Diffi culties in defi nition of the incidence of AKI are especially evident in searches for data from low-income and middle-income countries, where more than 85% of the world’s population resides. No nationwide data collection systems are available, and data are usually from isolated centres and probably largely underestimate the true extent of AKI because they mostly do not include patients with AKI who were not able to reach a hospital for treatment. A recent metaanalysis that included 312 cohort studies and more than 49 million patients shows a scarcity of data from Africa and large parts of southeast Asia. We did an updated meta-analysis that used the most recent KDIGO (Kidney Disease: Improving Global Outcomes) defi nitions, which confi rms the high incidence and resulting outcomes of AKI, particularly in Africa, Asia, and Latin America, for which data were previously absent. The strong relation between the severity of AKI and consequent mortality is reiterated by our fi ndings and is evident across heterogeneous populations and specifi c disease cohorts. However, large gaps remain in knowledge about the factors that aff ect the geographical variation of AKI and poor outcomes. Many diff erences exist in the aetiology, pathophysiology, and management of AKI across the world. In high-income countries, AKI develops mainly in patients in hospitals. In low-income and middle-income countries, AKI occurs mainly in the community setting in acute illness, usually in association with diarrhoeal states and dehydration, infections such as malaria, and toxins (venoms and poisons). Public health issues (eg, contaminated water, poor sanitation, endemic infections such as malaria and dengue fever, venomous snakes, and toxic traditional medicines) and socioeconomic factors (eg, availability of health-care facilities) aff ect the epidemiology of AKI. Additionally availability of trained personnel and access to diagnostic tests and dialysis aff ect practice patterns and impose barriers to care. The extent to which these factors contribute to mortality and non-recovery of renal function has not been quantifi ed. AKI is potentially preventable and treatable with timely intervention, but there continues to be a high human burden. Which specifi c factors account for the poor outcomes and to what extent variations in care delivery contribute are unclear. The ability to provide lifesaving treatments for AKI provides a compelling argument to consider therapy for AKI as much of a basic right as it is to give antiretroviral drugs to treat HIV in low-resource regions, especially because care needs only be given for a Published Online March 13, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60126-X

Clinical review: RIFLE and AKIN – time for reappraisal

In recent years, the use of the consensus definitions of acute kidney injury (RIFLE and AKIN) in the literature has increased substantially. This indicates a highly encouraging acceptance by the medical community of a unifying definition for acute kidney injury. This is a very important and positive step in the right direction. There remains some variation in how the criteria are interpreted and used in the literature, including use/nonuse of urine output criteria, use of change in estimated glomerular filtration rate rather than change in creatinine, and choice of baseline creatinine. The present review is intended to aid the reader in critically appraising studies using these consensus definitions. Since no single definition will be perfect, a logical next step would be to reconcile existing definitions, moving the medical community towards using a single consensus definition as has been done with sepsis and acute lung injury/acute respiratory distress syndrome. As new data emerge, integration of novel biomarkers into the consensus definition will be a welcome refinement.

Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conference

Over the last decade there has been considerable progress in the discovery and development of biomarkers of kidney disease, and several have now been evaluated in different clinical settings. While there is a growing literature on the performance of various biomarkers in clinical studies, there is limited information on how these biomarkers would be utilized by clinicians to manage patients with acute kidney injury (AKI). Recognizing this gap in knowledge, we convened the 10th Acute Dialysis Quality Initiative (ADQI) meeting to review the literature on biomarkers in AKI and their application in clinical practice. We asked an international group of experts to assess four broad areas for biomarker utilization for AKI: risk assessment, diagnosis and staging; differential diagnosis; prognosis and management and novel physiological techniques including imaging. This article provides a summary of the key findings and recommendations of the group, to equip clinicians to effectively use biomarkers in AKI.

Delivered dose of renal replacement therapy and mortality in critically ill patients with acute kidney injury

IntroductionThe optimal dialysis dose for the treatment of acute kidney injury (AKI) is controversial. We sought to evaluate the relationship between renal replacement therapy (RRT) dose and outcome.MethodsWe performed a prospective multicentre observational study in 30 intensive care units (ICUs) in eight countries from June 2005 to December 2007. Delivered RRT dose was calculated in patients treated exclusively with either continuous RRT (CRRT) or intermittent RRT (IRRT) during their ICU stay. Dose was categorised into more-intensive (CRRT ≥ 35 ml/kg/hour, IRRT ≥ 6 sessions/week) or less-intensive (CRRT < 35 ml/kg/hour, IRRT < 6 sessions/week). The main outcome measures were ICU mortality, ICU length of stay and duration of mechanical ventilation.ResultsOf 15,200 critically ill patients admitted during the study period, 553 AKI patients were treated with RRT, including 338 who received CRRT only and 87 who received IRRT only. For CRRT, the median delivered dose was 27.1 ml/kg/hour (interquartile range (IQR) = 22.1 to 33.9). For IRRT, the median dose was 7 sessions/week (IQR = 5 to 7). Only 22% of CRRT patients and 64% of IRRT patients received a more-intensive dose. Crude ICU mortality among CRRT patients were 60.8% vs. 52.5% (more-intensive vs. less-intensive groups, respectively). In IRRT, this was 23.6 vs. 19.4%, respectively. On multivariable analysis, there was no significant association between RRT dose and ICU mortality (Odds ratio (OR) more-intensive vs. less-intensive: CRRT OR = 1.21, 95% confidence interval (CI) = 0.66 to 2.21; IRRT OR = 1.50, 95% CI = 0.48 to 4.67). Among survivors, shorter ICU stay and duration of mechanical ventilation were observed in the more-intensive RRT groups (more-intensive vs. less-intensive for all: CRRT (median): 15 (IQR = 8 to 26) vs. 19.5 (IQR = 12 to 33.5) ICU days, P = 0.063; 7 (IQR = 4 to 17) vs. 14 (IQR = 5 to 24) ventilation days, P = 0.031; IRRT: 8 (IQR = 5.5 to 14) vs. 18 (IQR = 13 to 35) ICU days, P = 0.008; 2.5 (IQR = 0 to 10) vs. 12 (IQR = 3 to 24) ventilation days, P = 0.026).ConclusionsAfter adjustment for multiple variables, these data provide no evidence for a survival benefit afforded by higher dose RRT. However, more-intensive RRT was associated with a favourable effect on ICU stay and duration of mechanical ventilation among survivors. This result warrants further exploration.Trial RegistrationCochrane Renal Group (CRG110600093).