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Angiotensin II (ANGII) is a peptide that increases blood pressure and is part of the renin-angiotensin-aldosterone system (RAAS). It has recently been approved as a vasopressor drug for the treatment of vasodilatory hypotension and shock in the ICU. The ATHOS-3 trial demonstrated that ANGII was effective in increasing mean arterial pressure and achieving target blood pressure in patients with catecholamine-refractory vasodilatory shock. Subgroup analyses showed that ANGII was particularly beneficial for patients on renal replacement therapy and those with elevated plasma renin concentration. Further studies are needed to determine the optimal timing, patient selection, and duration of ANGII therapy, as well as its use in combination with other agents. [Extracted from the article]

Clinical trials are a dominant force in the field of clinical medicine and play a crucial role in informing global clinical practice. They utilize powerful concepts such as randomization, blinding, and statistical analysis to assess the safety and effectiveness of interventions. While clinical trials have some controversies, they have delivered significant advancements in treatments and have saved countless lives. Clinical trial networks have emerged as a valuable tool for collaboration among researchers, institutions, and key players in the research process. These networks address challenges such as patient recruitment, variability in processes, translation of research findings, and costs. They facilitate collaboration, standardize protocols, optimize resource utilization, and enhance the external validity of study findings. Despite some barriers, clinical trial networks represent a significant advancement in medical research and are crucial for the future of clinical trials. [Extracted from the article]

This document is a correspondence to the editor regarding an article on precision net ultrafiltration in continuous renal replacement therapy (CRRT). The authors express concern about the use of terminology in the article and argue that the main author subverts the definition of net ultrafiltration (NUF) and destabilizes the accepted consensus nomenclature. They criticize the article for confusing NUF with fluid balance and making adjustments based on incomplete fluid balance. The authors call for the adoption of accepted terminology in future research. The document also includes acknowledgements and author contributions. [Extracted from the article]

Intensive care unit (ICU) patients with end-organ failure will require specialised machines or extracorporeal therapies to support the failing organs that would otherwise lead to death. ICU patients with severe acute kidney injury may require renal replacement therapy (RRT) to remove fluid and wastes from the body, and patients with severe cardiorespiratory failure will require extracorporeal membrane oxygenation (ECMO) to maintain adequate oxygen delivery whilst the underlying pathology is evaluated and managed. The presence of ECMO and RRT machines can further augment the existing pharmacokinetic (PK) alterations during critical illness. Significant changes in the apparent volume of distribution (Vd) and drug clearance (CL) for many important drugs have been reported during ECMO and RRT. Conventional antimicrobial dosing regimens rarely consider the impact of these changes and consequently, are unlikely to achieve effective antimicrobial exposures in critically ill patients receiving ECMO and/or RRT. Therefore, an in-depth understanding on potential PK changes during ECMO and/or RRT is required to inform antimicrobial dosing strategies in patients receiving ECMO and/or RRT. In this narrative review, we aim to discuss the potential impact of ECMO and RRT on the PK of antimicrobials and antimicrobial dosing requirements whilst receiving these extracorporeal therapies. The potential benefits of therapeutic drug monitoring (TDM) and dosing software to facilitate antimicrobial therapy for critically ill patients receiving ECMO and/or RRT are also reviewed and highlighted. [ABSTRACT FROM AUTHOR]

Purpose: Acute illness severity predicts mortality in intensive care unit (ICU) patients, however, its predictive value decreases over time in ICU. Typically after 10 days, pre-ICU (antecedent) characteristics become more predictive of mortality, defining the onset of persistent critical illness (PerCI). How patient frailty affects development and death from PerCI is unknown. Methods: We conducted a secondary analysis of data from a prospective binational cohort study including 269,785 critically ill adults from 168 ICUs in Australia and New Zealand, investigating whether frailty measured with the Clinical Frailty Scale (CFS) changes the timing of onset and risk of developing PerCI and of subsequent in-hospital mortality. We assessed associations between frailty (CFS ≥ 5) and mortality prediction using logistic regression and area under the receiver operating characteristics (AUROC) curves. Results: 2190 of 50,814 (4.3%) patients with frailty (CFS ≥ 5) versus 6624 of 218,971 (3%) patients without frailty (CFS ≤ 4) developed PerCI (P < 0.001). Among patients with PerCI, 669 of 2190 (30.5%) with frailty and 1194 of 6624 without frailty (18%) died in hospital (P < 0.001). The time point defining PerCI onset did not vary with frailty degree; however, with increasing length of ICU stay, inclusion of frailty progressively improved mortality discrimination (0.1% AUROC improvement on ICU day one versus 3.6% on ICU day 17). Conclusion: Compared to patients without frailty, those with frailty have a higher chance of developing and dying from PerCI. Moreover the importance of frailty as a predictor of mortality increases with ICU length of stay. Future work should explore incorporation of frailty in prognostic models, particularly for long-staying patients. [ABSTRACT FROM AUTHOR]

Sepsis induced by bacteria or viruses can result in multiorgan dysfunction, which is a major cause of death in intensive care units. Current treatments are only supportive, and there are no treatments that reverse the pathophysiological effects of sepsis. Vitamin C has antioxidant, anti‐inflammatory, anticoagulant and immune modulatory actions, so it is a rational treatment for sepsis. Here, we summarise data that support the use of megadose vitamin C as a treatment for sepsis and COVID‐19. Megadose intravenous sodium ascorbate (150 g per 40 kg over 7 h) dramatically improved the clinical state and cardiovascular, pulmonary, hepatic and renal function and decreased body temperature, in a clinically relevant ovine model of Gram‐negative bacteria‐induced sepsis. In a critically ill COVID‐19 patient, intravenous sodium ascorbate (60 g) restored arterial pressure, improved renal function and increased arterial blood oxygen levels. These findings suggest that megadose vitamin C should be trialled as a treatment for sepsis and COVID‐19. [ABSTRACT FROM AUTHOR]

Background: Frailty is associated with poor outcomes in critical illness. However, it is unclear whether frailty screening on admission to the ICU can be conducted routinely at the population level and whether it has prognostic importance.Research Question: Can population-scale frailty screening with the Clinical Frailty Scale (CFS) be implemented for critically ill adults in Australia and New Zealand (ANZ) and can it identify patients at risk of negative outcomes?Study Design and Methods: We conducted a binational prospective cohort study of critically ill adult patients admitted between July 1, 2018, and June 30, 2020, in 175 ICUs in ANZ. We classified frailty with the CFS on admission to the ICU. The primary outcome was in-hospital mortality; secondary outcomes were length of stay (LOS), discharge destination, complications (delirium, pressure injury), and duration of survival.Results: We included 234,568 critically ill patients; 45,245 (19%) were diagnosed as living with frailty before ICU admission. Patients with vs without frailty had higher in-hospital mortality (16% vs 5%; P < .001), delirium (10% vs 4%; P < .001), longer LOS in the ICU and hospital, and increased new chronic care discharge (3% vs 1%; P < .001), with worse outcomes associated with increasing CFS category. Of patients with very severe frailty (CFS score, 8), 39% died in hospital vs 2% of very fit patients (CFS score, 1; multivariate categorical CFS score, 8 [reference, 1]; OR, 7.83 [95% CI, 6.39-9.59]; P < .001). After adjustment for illness severity, frailty remained highly significantly predictive of mortality, including among patients younger than 50 years, with improvement in the area under the receiver operating characteristic curve of the Acute Physiology and Chronic Health Evaluation III-j score to 0.882 (95% CI, 0.879-0.885) from 0.868 (95% CI, 0.866-0.871) with the addition of frailty (P < .001).Interpretation: Large-scale population screening for frailty degree in critical illness was possible and prognostically important, with greater frailty (especially CFS score of ≥ 6) associated with worse outcomes, including among younger patients. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has led to unprecedented demand for ICUs, with the need to triage admissions along with the development of ICU triage criteria. However, how these criteria relate to outcomes in patients already admitted to the ICU is unknown, as is the incremental ICU capacity that triage of these patients might create given existing admission practices.Research Question: What is the short- and long-term survival of low- vs high-priority patients for ICU admission according to current pandemic triage criteria?Study Design and Methods: This study analyzed prospectively collected registry data (2007-2018) in 23 ICUs in Victoria, Australia, with probabilistic linkage with death registries. After excluding elective surgery, admissions were stratified according to existing ICU triage protocol prioritization as low (age ≥ 85 years, or severe chronic illness, or Sequential Organ Failure Assessment [SOFA] score = 0 or ≥ 12), medium (SOFA score = 8-11) or high (SOFA score = 1-7) priority. The primary outcome was long-term survival. Secondary outcomes were in-hospital mortality, ICU length of stay (LOS) and bed-day usage.Results: This study examined 126,687 ICU admissions. After 5 years of follow-up, 1,093 of 3,296 (33%; 95% CI, 32-34) of "low-priority" patients aged ≥ 85 years or with severe chronic illness and 86 of 332 (26%; 95% CI, 24-28) with a SOFA score ≥ 12 were still alive. Sixty-three of 290 (22%; 95% CI, 17-27) of patients in these groups followed up for 10 years were still alive. Together, low-priority patients accounted for 27% of all ICU bed-days and had lower in-hospital mortality (22%) than the high-priority patients (28%). Among nonsurvivors, low-priority admissions had shorter ICU LOS than medium- or high-priority admissions.Interpretation: Current SOFA score or age or severe comorbidity-based ICU pandemic triage protocols exclude patients with a close to 80% hospital survival, a > 30% five-year survival, and 27% of ICU bed-day use. These findings imply the need for stronger evidence-based ICU triage protocols. [ABSTRACT FROM AUTHOR]

Furthermore, accounting for competing risks is also an important consideration for secondary outcomes as mortality impacts duration of mechanical ventilation and/or intensive care length of stay. Evidence from a randomized study of adults with septic shock suggests that fluid restrictive strategies reduce fluid administration but not mortality or days free from intensive care supports ([5]). In an international, multicentre study of over 5,000 children and young adults, Selewski et al ([1]) report the epidemiology and adverse outcomes associated with thresholds of fluid accumulation in terms of magnitude and timing. [Extracted from the article]

Furthermore, the suggested effect size for an improvement in functional outcome due to this intervention is greater than 25% [[1]], and still more than 15% greater than the outcome reported in EPO-TBI [[3]]. Effect sizes in ongoing randomised controlled critical care trials. This is compounded by the observation that approximately 50% of the patients in each group experienced a degree of pneumonitis, although the aetiology of this is unclear from the manuscript, with no information on hospital- or ventilator-associated infections being presented [[1]]. [Extracted from the article]

Management of fluid overload is one of the most challenging problems in the care of critically ill patients with oliguric acute kidney injury. Various clinical practice guidelines support fluid removal using ultrafiltration during kidney replacement therapy. However, ultrafiltration is associated with considerable risks. Emerging evidence from observational studies suggests that both slow and fast rates of net fluid removal (that is, net ultrafiltration (UFNET)) during continuous kidney replacement therapy are associated with increased mortality compared with moderate UFNET rates. In addition, fast UFNET rates are associated with an increased risk of cardiac arrhythmias. Experimental studies in patients with kidney failure who were treated with intermittent haemodialysis suggest that fast UFNET rates are also associated with ischaemic injury to the heart, brain, kidney and gut. The UFNET rate should be prescribed based on patient body weight in millilitres per kilogramme per hour with close monitoring of patient haemodynamics and fluid balance. Dialysate cooling and sodium modelling may prevent haemodynamic instability and facilitate large volumes of fluid removal in patients with kidney failure who are treated with intermittent haemodialysis, but the effects of this strategy on organ injury are less well studied in critically ill patients treated with continuous kidney replacement therapy. Randomized trials are required to examine whether moderate UFNET rates are associated with a reduced risk of haemodynamic instability, organ injury and improved outcomes in critically ill patients. [ABSTRACT FROM AUTHOR]

Modern CRRT machines can deliver therapy that resembles IHD, and IHD treatments can be slowed to deliver therapy over 10-12 hours, which resembles CRRT. Bellomo R, Cass A, Cole L, et al; RENAL Replacement Therapy Study Investigators: Intensity of continuous renalreplacement therapy in critically ill patients. RRT was performed in 96.8% of accelerated-strategy patients and 61.8% of patients in the standard therapy patients, where RRT was discouraged unless conventional indications developed or AKI persisted for greater than 72 hours. Initially, dialysis nurses were consulted for ICU patients, but due to their high workload, they were often unable to respond in a timely manner to the increasing needs associated with a therapy that was delivered 24 hr/d in sicker and sicker patients. [Extracted from the article]

Background: A threshold Clinical Frailty Scale (CFS) of 5 (indicating mild frailty) has been proposed to guide ICU admission for UK patients with coronavirus disease 2019 (COVID-19) pneumonia. However, the impact of frailty on mortality with (non-COVID-19) pneumonia in critical illness is unknown. We examined the triage utility of the CFS in patients with pneumonia requiring ICU.Methods: We conducted a retrospective cohort study of adult patients admitted with pneumonia to 170 ICUs in Australia and New Zealand from January 1, 2018 to September 31, 2019. We classified patients as: non-frail (CFS 1-4) frail (CFS 5-8), mild/moderately frail (CFS 5-6),and severe/very severely frail (CFS 7-8). We evaluated mortality (primary outcome) adjusting for site, age, sex, mechanical ventilation, pneumonia type and illness severity. We also compared the proportion of ICU bed-days occupied between frailty categories.Results: 1852/5607 (33%) patients were classified as frail, including1291/3056 (42%) of patients aged >65 yr, who would potentially be excluded from ICU admission under UK-based COVID-19 triage guidelines. Only severe/very severe frailty scores were associated with mortality (adjusted odds ratio [aOR] for CFS=7: 3.2; 95% confidence interval [CI]: 1.3-7.8; CFS=8 [aOR: 7.2; 95% CI: 2.6-20.0]). These patients accounted for 7% of ICU bed days. Vulnerability (CFS=4) and mild frailty (CFS=5) were associated with a similar mortality risk (CFS=4 [OR: 1.6; 95% CI: 0.7-3.8]; CFS=5 [OR: 1.6; 95% CI: 0.7-3.9]).Conclusions: Patients with severe and very severe frailty account for relatively few ICU bed days as a result of pneumonia, whilst adjusted mortality analysis indicated little difference in risk between patients in vulnerable, mild, and moderate frailty categories. These data do not support CFS ≥5 to guide ICU admission for pneumonia. [ABSTRACT FROM AUTHOR]

Background: The perioperative use of vasoactive drugs is ubiquitous in clinical anaesthesia; yet, the drugs, doses, and haemodynamic targets used are highly variable. Our objectives were to determine whether the perioperative administration of vasoactive drugs reduces mortality, morbidity, and length of stay in adult patients (aged 16 yr or older) undergoing major abdominal surgery.Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for peer-reviewed RCTs with no language or date restrictions. Studies that assessed the intraoperative use of vasoactive drugs were included. Title, abstract, and full-text screening was performed. Risk of bias for each outcome measure was conducted. We calculated the risk ratio (RR) using the Mantel-Haenszel random-effects model with corresponding 95% confidence interval (CI) for dichotomous outcomes, and mean difference using the inverse variance random-effects model with corresponding 95% CI for continuous outcomes.Results: Twenty-six studies (5561 participants) were included. There was no difference in mortality at the longest follow-up with an RR of 0.84 (95% CI: 0.63-1.12; P=0.23). The intervention significantly reduced the number of patients with one or more postoperative complications; RR: 0.76 (95% CI: 0.66-0.88; P=0.0002). Hospital length of stay was reduced by 0.91 days in the intervention group.Conclusions: This review is limited by the quality and sample size of individual studies, and the heterogeneity of the settings, interventions, and outcome measures. Perioperative administration of vasoactive drugs may reduce postoperative complications and hospital length of stay in adult patients having major abdominal surgery. [ABSTRACT FROM AUTHOR]

Patients who are undergoing mechanical ventilation in the intensive care unit (ICU) often receive a high fraction of inspired oxygen (Fio) and have a high arterial oxygen tension. The conservative use of oxygen may reduce oxygen exposure, diminish lung and systemic oxidative injury, and thereby increase the number of ventilator-free days (days alive and free from mechanical ventilation). METHODS We randomly assigned 1000 adult patients who were anticipated to require mechanical ventilation beyond the day after recruitment in the ICU to receive conservative or usual oxygen therapy. In the two groups, the default lower limit for oxygen saturation as measured by pulse oximetry (Spo2) was 90%. In the conservativeoxygen group, the upper limit of the Spo2 alarm was set to sound when the level reached 97%, and the Fio2 was decreased to 0.21 if the Spo2 was above the acceptable lower limit. In the usual-oxygen group, there were no specific measures limiting the Fio2 or the Spo2. The primary outcome was the number of ventilatorfree days from randomization until day 28. RESULTS The number of ventilator-free days did not differ significantly between the conservative- oxygen group and the usual-oxygen group, with a median duration of 21.3 days (interquartile range, 0 to 26.3) and 22.1 days (interquartile range, 0 to 26.2), respectively, for an absolute difference of -0.3 days (95% confidence interval [Cl], -2.1 to 1.6; P=0.80). The conservative-oxygen group spent more time in the ICU with an Fio2 of 0.21 than the usual-oxygen group, with a median duration of 29 hours (interquartile range, 5 to 78) and 1 hour (interquartile range, 0 to 17), respectively (absolute difference, 28 hours; 95% Cl, 22 to 34); the conservative-oxygen group spent less time with an Spo2 exceeding 96%, with a duration of 27 hours (interquartile range, 11 to 63.5) and 49 hours (interquartile range, 22 to 112), respectively (absolute difference, 22 hours; 95% Cl, 14 to 30). At 180 days, mortality was 35.7% in the conservative-oxygen group and 34.5% in the usual-oxygen group, for an unadjusted odds ratio of 1.05 (95% Cl, 0.81 to 1.37). CONCLUSIONS In adults undergoing mechanical ventilation in the ICU, the use of conservative oxygen therapy, as compared with usual oxygen therapy, did not significantly affect the number of ventilator-free days. (Funded by the New Zealand Health Research Council; ICU-ROX Australian and New Zealand Clinical Trials Registry number, ACTRN12615000957594.) [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is defined by a rapid increase in serum creatinine, decrease in urine output, or both. AKI occurs in approximately 10-15% of patients admitted to hospital, while its incidence in intensive care has been reported in more than 50% of patients. Kidney dysfunction or damage can occur over a longer period or follow AKI in a continuum with acute and chronic kidney disease. Biomarkers of kidney injury or stress are new tools for risk assessment and could possibly guide therapy. AKI is not a single disease but rather a loose collection of syndromes as diverse as sepsis, cardiorenal syndrome, and urinary tract obstruction. The approach to a patient with AKI depends on the clinical context and can also vary by resource availability. Although the effectiveness of several widely applied treatments is still controversial, evidence for several interventions, especially when used together, has increased over the past decade. [ABSTRACT FROM AUTHOR]

The article offers information on the study regarding the micronutrient deficiency in critical illness. Topics discussed include information on the micronutrient preventing refeeding‑related morbidity and mortality; discussions on the initiation of artificial nutrition, develop a significant decrease in serum phosphate levels and hypophosphatemia; and the role of Vitamin C and vitamin D in the human body.

This article explores the potential use of renin as a biomarker in sepsis. Renin is an enzyme involved in regulating various physiological processes. Some studies have found associations between renin levels and sepsis outcomes, including mortality. However, these studies have limitations such as small sample sizes and lack of external validation. While renin shows promise as a biomarker, further research is needed to confirm its usefulness in clinical care. The article also discusses the potential use of renin levels to guide the administration of angiotensin II in septic shock, but more research is needed to determine reference ranges and thresholds for clinical action. Overall, there is a need for a better understanding of the renin-angiotensin system and the development of biomarkers to inform clinical decision-making. [Extracted from the article]

An editorial is presented on the novel renal biomarkers of acute kidney injury and their implications. The article discusses that the Acute kidney injury (AKI) is a common problem in the community, in hospitalized patients and on a global scale; it is independently associated with increased morbidity, mortality and risk of subsequent chronic kidney disease; and the diagnosis of AKI and its consensus definition rest on criteria that is the serum creatinine concentration and urinary output.

The article discusses the removal of a substance from blood, expressed as a volume over time called lactate clearance. It cites on the changes in lactate levels in the production and removal from the blood by excretion through urine and sweat. The article also discusses the review of several studies which concluded given evidence and measurement that would give data that decrease in lactate levels.

Aim: Common blood tests can help identify patients at risk of death, unplanned intensive care unit (ICU) admission, or rapid response team (RRT) call. We aimed to test whether early ICU-team review triggered by such laboratory tests (lab alert) is feasible, safe, and can alter physiological variables, clinical management, and clinical outcomes.Methods: In prospective pilot randomized controlled trial in surgical wards of a tertiary hospital, we studied patients admitted for >24 h. We applied a previously validated risk assessment tool to each set of common laboratory tests to identify patients at risk and generate a "lab-alert". We randomly allocated such lab-alert patients to receive early ICU-team review (intervention) or usual care (control).Results: We studied 205 patients (males 54.1%; average age 79 years; 103 randomized to intervention and 102 to usual care). Intervention patients were more likely to trigger RRT activation during their first lab-alert (10.7 vs. 2.0%; P < 0.001) but less likely to receive an allied health referral (18.0% vs. 24.5%; p = 0.007). They were less likely to trigger RRT activation in the 24-h before subsequent alerts (18.4 vs. 22.4%; p = 0.008) and less likely to generate further alerts (204 vs. 320; p < 0.001), but more likely to receive a not for resuscitation or endotracheal intubation status in the 24-h before subsequent alerts (26.6 vs. 17.3%; p = 0.05). Mortality at 24 h was 1.9% for the intervention group vs. 2.9% in the control group (p = 0.63). Finally, overall mortality was 19.4% for intervention patients vs. 23.5% for control patients (p = 0.50).Conclusion: Among surgical patients, lab alerts identify patients with a high mortality. Lab alert-triggered interventions are associated with more first alert-associated RRT activations; more changes in resuscitation status toward a more conservative approach; fewer subsequent alert-associated RRT activations; fewer subsequent alerts, and decreased allied health interventions (ANZCTRN12615000146594). [ABSTRACT FROM AUTHOR]

Two recent randomized trials provide evidence to guide the management of sepsis. The CLASSIC trial reports that restrictive fluid therapy has no mortality benefit compared to a standard regimen in patients with septic shock, whereas the LOVIT trial reports that high-dose intravenous vitamin C might be harmful in patients with severe sepsis. [ABSTRACT FROM AUTHOR]

Large studies during the coronavirus disease 2019 (COVID-19) pandemic have also shown that frailty, measured by the CFS in patients aged < 65 years, is associated with higher mortality [[4]]. We thank Shah and colleagues for the points they raise [[1]] regarding our study examining frailty and persistent critical illness [[2]]. [Extracted from the article]

Objectives: In the absence of a universal definition of light or deep sedation, the level of sedation that conveys favorable outcomes is unknown. We quantified the relationship between escalating intensity of sedation in the first 48 hours of mechanical ventilation and 180-day survival, time to extubation, and delirium. Design: Harmonized data from prospective multicenter international longitudinal cohort studies Setting: Diverse mix of ICUs. Patients: Critically ill patients expected to be ventilated for longer than 24 hours. Interventions: Richmond Agitation Sedation Scale and pain were assessed every 4 hours. Delirium and mobilization were assessed daily using the Confusion Assessment Method of ICU and a standardized mobility assessment, respectively. Measurements and Main Results: Sedation intensity was assessed using a Sedation Index, calculated as the sum of negative Richmond Agitation Sedation Scale measurements divided by the total number of assessments. We used multivariable Cox proportional hazard models to adjust for relevant covariates. We performed subgroup and sensitivity analysis accounting for immortal time bias using the same variables within 120 and 168 hours. The main outcome was 180-day survival. We assessed 703 patients in 42 ICUs with a mean (sd) Acute Physiology and Chronic Health Evaluation II score of 22.2 (8.5) with 180-day mortality of 32.3% (227). The median (interquartile range) ventilation time was 4.54 days (2.47–8.43 d). Delirium occurred in 273 (38.8%) of patients. Sedation intensity, in an escalating dose-dependent relationship, independently predicted increased risk of death (hazard ratio [95% CI], 1.29 [1.15–1.46]; p < 0.001, delirium hazard ratio [95% CI], 1.25 [1.10–1.43]), p value equals to 0.001 and reduced chance of early extubation hazard ratio (95% CI) 0.80 (0.73–0.87), p value of less than 0.001. Agitation level independently predicted subsequent delirium hazard ratio [95% CI], of 1.25 (1.04–1.49), p value equals to 0.02. Delirium or mobilization episodes within 168 hours, adjusted for sedation intensity, were not associated with survival. Conclusions: Sedation intensity independently, in an ascending relationship, predicted increased risk of death, delirium, and delayed time to extubation. These observations suggest that keeping sedation level equivalent to a Richmond Agitation Sedation Scale 0 is a clinically desirable goal. [ABSTRACT FROM AUTHOR]

The hemodynamic effects of intravenous (IV) paracetamol in patients undergoing cardiac surgery are unknown. We performed a prospective single center placebo controlled randomized study with parallel group design in adult patients undergoing elective cardiac surgery. Participants received paracetamol (1 gram) IV or placebo (an equal volume of 0.9% saline) preoperatively followed by two postoperative doses 6 hours apart. The primary endpoint was the absolute change in systolic (SBP) 30 minutes after the preoperative infusion, analysed using an ANCOVA model. Secondary endpoints included absolute changes in mean arterial pressure (MAP) and diastolic blood pressure (DPB), and other key hemodynamic variables after each infusion. All other endpoints were analysed using random-effect generalized least squares regression modelling with individual patients treated as random effects. Fifty participants were randomly assigned to receive paracetamol (n = 25) or placebo (n = 25). Post preoperative infusion, paracetamol decreased SBP by a mean (SD) of 13 (18) mmHg, p = 0.02, compared to a mean (SD) of 1 (11) mmHg with saline. Paracetamol decreased MAP and DBP by a mean (SD) of 9 (12) mmHg and 8 (9) mmHg (p = 0.01 and 0.02), respectively, compared to a mean (SD) of 1 (8) mmHg and 0 (6) mmHg with placebo. Postoperatively, there were no significant differences in pressure or flow based hemodynamic parameters in both groups. This study provides high quality evidence that the administration of IV paracetamol in patients undergoing cardiac surgery causes a transient decrease in preoperative blood pressure when administered before surgery but no adverse hemodynamic effects when administered in the postoperative setting. [ABSTRACT FROM AUTHOR]

Objective Patients commonly receive i.v. fluids in the ED. It is still unclear whether the choice of i.v. fluids in this setting influences renal or patient outcomes. We aimed to assess the effects of restricting i.v. chloride administration in the ED on the incidence of acute kidney injury ( AKI). Methods We conducted a before-and-after trial with 5008 consecutive ED-treated hospital admissions in the control period and 5146 consecutive admissions in the intervention period. During the control period (18 February 2008 to 17 August 2008), patients received standard i.v. fluids. During the intervention period (18 February 2009 to 17 August 2009), we restricted all chloride-rich fluids. We used the Kidney Disease: Improving Global Outcomes ( KDIGO) staging to define AKI. Results Stage 3 of KDIGO-defined AKI decreased from 54 (1.1%; 95% confidence interval [ CI] 0.8-1.4) to 30 (0.6%; 95% CI 0.4-0.8) ( P = 0.006). The rate of renal replacement therapy did not change, from 13 (0.3%; 95% CI 0.2-0.4) to 8 (0.2%; 95% CI 0.1-0.3) ( P = 0.25). After adjustment for relevant covariates, liberal chloride therapy remained associated with a greater risk of KDIGO stage 3 (hazard ratio 1.82; 95% CI 1.13-2.95; P = 0.01). On sensitivity assessment after removing repeat admissions, KDIGO stage 3 remained significantly lower in the intervention period compared with the control period ( P = 0.01). Conclusion In a before-and-after trial, a chloride-restrictive strategy in an ED was associated with a significant decrease in the incidence of stage 3 of KDIGO-defined AKI. [ABSTRACT FROM AUTHOR]

Cardiac surgery-associated acute kidney injury (CSA-AKI) is the most common clinically important complication in adult patients undergoing open heart surgery, and is associated with increased mortality and morbidity. In patients in intensive care units, CSA-AKI is the second most common type of AKI after septic AKI. In this Review, we explore the definition of CSA-AKI, discuss its epidemiology and identify its risk factors. We discuss current theories of the pathophysiology of CSA-AKI and describe its clinical course. Furthermore, we introduce diagnostic tools with particular reference to novel biomarkers of AKI and their potential utility; we analyse currently applied interventions aimed at attenuating AKI in patients undergoing cardiac surgery; and describe evidence from randomized controlled trials aimed at preventing or treating CSA-AKI. Finally, we explore issues in the use of renal replacement therapy, its timing, its intensity and its preferred modalities in patients with CSA-AKI, and we discuss the prognosis of CSA-AKI in terms of patient survival and kidney recovery. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) and sepsis carry consensus definitions. The simultaneous presence of both identifies septic AKI. Septic AKI is the most common AKI syndrome in ICU and accounts for approximately half of all such AKI. Its pathophysiology remains poorly understood, but animal models and lack of histological changes suggest that, at least initially, septic AKI may be a functional phenomenon with combined microvascular shunting and tubular cell stress. The diagnosis remains based on clinical assessment and measurement of urinary output and serum creatinine. However, multiple biomarkers and especially cell cycle arrest biomarkers are gaining acceptance. Prevention of septic AKI remains based on the treatment of sepsis and on early resuscitation. Such resuscitation relies on the judicious use of both fluids and vasoactive drugs. In particular, there is strong evidence that starch-containing fluids are nephrotoxic and decrease renal function and suggestive evidence that chloride-rich fluid may also adversely affect renal function. Vasoactive drugs have variable effects on renal function in septic AKI. At this time, norepinephrine is the dominant agent, but vasopressin may also have a role. Despite supportive therapies, renal function may be temporarily or completely lost. In such patients, renal replacement therapy (RRT) becomes necessary. The optimal intensity of this therapy has been established, while the timing of when to commence RRT is now a focus of investigation. If sepsis resolves, the majority of patients recover renal function. Yet, even a single episode of septic AKI is associated with increased subsequent risk of chronic kidney disease. [ABSTRACT FROM AUTHOR]

The article provides information on the renal functional reserve (RFR), which refers to the capacity of the kidney to respond to physiological demands, and its role and importance in physiology and disease. It describes the role of RFR in determining the kidney's capacity to increase the glomerular filtration rate (GFR) by nephron recruitment and increases in renal blood flow coupled with hyperfiltration. It also discusses the relevance of RFR to intensive care medicine.

The French Intensive Care Society organized its yearly Paris International Conference in intensive care on June 18-19, 2015. The main purpose of this meeting is to gather the best experts in the field in order to provide the highest quality update on a chosen topic. In 2015, the selected theme was: 'Acute Renal Failure in the ICU: from injury to recovery.' The conference program covered multiple aspects of renal failure, including epidemiology, diagnosis, treatment and kidney support system, prognosis and recovery together with acute renal failure in specific settings. The present report provides a summary of every presentation including the key message and references and is structured in eight sections: (a) diagnosis and evaluation, (b) old and new diagnosis tools, (c) old and new treatments, (d) renal replacement therapy and management, (e) acute renal failure witness of other conditions, (f) prognosis and recovery, (g) extracorporeal epuration beyond the kidney, (h) the use of biomarkers in clinical practice . [ABSTRACT FROM AUTHOR]

Urinary examination has formed part of patient assessment since the earliest days of medicine. Current definitions of oliguria are essentially arbitrary, but duration and intensity of oliguria have been associated with an increased risk of mortality, and this risk is not completely attributable to the development of concomitant acute kidney injury (AKI) as defined by changes in serum creatinine concentration. The increased risk of death associated with the development of AKI itself may be modified by directly or indirectly by progressive fluid accumulation, due to reduced elimination and increased fluid administration. None of the currently extant major illness severity scoring systems or outcome prediction models use modern definitions of AKI or oliguria, or any values representative of fluid volumes variables. Even if a direct relationship with mortality is not observed, then it is possible that fluid balance or fluid volume variables mediate the relationship between illness severity and mortality in the renal and respiratory physiological domains. Fluid administration and fluid balance may then be an important, easily modifiable therapeutic target for future investigation. These relationships require exploration in large datasets before being prospectively validated in groups of critically ill patients from differing jurisdictions to improve prognostication and mortality prediction. [ABSTRACT FROM AUTHOR]

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of >90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD. [ABSTRACT FROM AUTHOR]

In clinical research, there has been an increasing need to titrate ethical, legal and insurance requirements to the type of study, so that higher-risk research receives necessary and appropriate detailed attention, while low-risk studies can proceed more rapidly. Spontaneous Medically Advantageous Research Trials (SMART) are non-profit studies that carry minimal or no risk to patients. This type of investigation, however, is currently hampered by the fact that, in many hospitals and jurisdictions it has to undergo the same bureaucratic procedures and safety assessments as high-risk, for-profit studies. We strongly believe that such practice of scientific research assessment should be radically modified. We advocate a new, specific research category for SMART investigations that grants them a preferential route from conception to ethics assessment to execution. In addition, we argue that such low risk studies assessing common, often not evidencebased applied treatments or investigations should in fact be a mandatory component of modern medicine. All clinicians, scientists, patients, patient associations, politicians, scientific associations and common citizens should be involved in this process, as they all play a crucial role in its evolution and success. We contend that modern medical research and entire health systems should transition to a novel model of healthcare system where SMART execution is embedded into daily practice, in order to minimize anecdotal practice and maximize evidencebased practice. [ABSTRACT FROM AUTHOR]

Despite near ubiquity, information regarding fluids consumption at a health care systems level, and patient exposure at an individual level, is surprisingly limited in the medical literature. The epidemiology of the foundational medical intervention of intravenous fluid administration is incredibly complex, with millions of patients being exposed internationally every year. Fluid is being given for different reasons, to different targets, following different triggers, by different specialties in different countries, and any observations that can be made are thought to have limited external validity to other jurisdictions and patient groups. The independent effects of fluid administration and fluid accumulation are very hard to separate from other markers of illness severity and aspects of the process of care. Fluid accumulation can result in organ injury, even when the fluid is being given to purportedly ameliorate or prevent such injury, and if it were independently associated with mortality then would be an easily accessible and modifiable risk factor for subsequent morbidity or death. Despite their ubiquity, it is clear that we have limited understanding of the effects of the intravenous fluids we use daily in the most vulnerable of patient groups. The research agenda in this field is large and urgent. [ABSTRACT FROM AUTHOR]

The article describes how the rise of ward monitoring creates opportunities and challenges for critical care specialists. It notes that the information has to be displayed on central stations and, when appropriate, redirected to the clinician in charge via a notification system. It adds that there are several technical challenges to the implementation of wireless and wearable monitoring systems on the wards.

An editorial is presented which focuses on the reliability of data used in clinical research to provide quality care for patients at the lowest possible cost. It cites on the importance of trustworthiness on research findings as not to harm patients and waste resources. The editorial also presents the harmful intervention in clinical use such as tight glycaemic control, hydroxyethyl starch and high-frequency oscillatory ventilation.

Objective: To assess the epidemiology and outcomes associated with RBC transfusion in patients with severe acute kidney injury requiring continuous renal replacement therapy.Design: Post hoc analysis of data from a multicenter, randomized, controlled trial.Setting: Thirty-five ICUs in Australia and New Zealand.Patients: Cohort of 1,465 patients enrolled in the Randomized Evaluation of Normal versus Augmented Level replacement therapy study.Interventions: Daily information on morning hemoglobin level and amount of RBC transfused were prospectively collected in the Randomized Evaluation of Normal versus Augmented Level study. We analyzed the epidemiology of such transfusions and their association with clinical outcomes.Measurements and Main Results: Overall, 977 patients(66.7%) received a total of 1,192 RBC units. By day 5, 785 of 977 transfused patients (80.4%) had received at least one RBC transfusion. Hemoglobin at randomization was lower in transfused than in nontransfused patients (94 vs 111 g/L; p < 0.001). Mean daily hemoglobin was 88 ± 7 and 99 ± 12 g/L in transfused and nontransfused patients. Among transfused patients, 228 (46.7%) had died by day 90 when compared with 426 (43.6%) of nontransfused patients (p = 0.27). Survivors received on average 316 ± 261 mL of RBC, whereas nonsurvivors received 302 ± 362 mL (p = 0.42). On multivariate Cox regression analysis, RBC transfusion was independently associated with lower 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79). However, we found no independent association between RBC transfusions and mortality when the analyses were restricted to patients surviving at least 5 days (hazard ratio, 1.29; 95% CI, 0.90-1.85). We found no independent association between RBC transfusion and renal replacement therapy-free days, mechanical ventilator-free days, or length of stay in ICU or hospital.Conclusions: In patients with severe acute kidney injury treated with continuous renal replacement therapy, we found no association of RBC transfusion with 90-day mortality or other patient-centered outcomes. The optimal hemoglobin threshold for RBC transfusion in such patients needs to be determined in future randomized controlled trials. [ABSTRACT FROM AUTHOR]

Aims: The study aims to describe the use of dialysis catheters in critically ill patients treated with continuous renal replacement therapy (CRRT) and to study the impact of femoral versus non-femoral access on CRRT dose. Methods: Statistical analysis and predictive modelling of data from the Randomized Evaluation of Normal vs. Augmented Level renal replacement therapy trial. Results: The femoral vein was the first access site in 937 (67%) of 1,399 patients. These patients had higher Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment scores (p = 0.009) and lower pH (p < 0.001) but similar mortality to patients with non-femoral access (44 vs. 45%; p = 0.63). Lower body weight was independently associated with femoral access placement (OR 0.97, 95% CI 0.96-0.98). Femoral access was associated with a 1.03% lower CRRT dose (p = 0.05), but a 4.20% higher dose was achieved with 13.5 Fr catheters (p = 0.03). Conclusions: Femoral access was preferred in lighter and sicker patients. Catheter gauge had greater impact than catheter site in CRRT dose delivery. [ABSTRACT FROM AUTHOR]

An editorial is presented in which the editor mentions the Australian and New Zealand's Intensive Care Research Centre (ANZIC-RC) which is the Australian National Health and Medical Research Council and Monash University funded bi-national centre for the development and coordination of multicentre randomized controlled trials (RCTs) in critically ill patients. He mentions research conducted by ANZIC-RC in every aspect of critical care medicine and commitment to international collaborations.

The article describes the case of a 66 year old female patient presented with fever, cough and right lower lobe infiltrate. The doctor was concerned about her serum creatinine of 1.3mg/dl indicating she may have a kidney disease. It provides a checklist that may help clinicians make the correct diagnosis for acute kidney injury (AKI). It suggests that the patient may have AKI but this is a provisional diagnosis and clinicians can change their diagnosis as more information becomes available.

Objective: We tested the hypothesis that responses to physiologic deterioration in hospital ward patients delayed by more than 15 minutes are associated with increased mortality.Design, Setting, and Participants: We used data from a 23-hospital cluster randomized trial (January 2004 to December 2004) of implementation of rapid response teams (intervention) versus standard practice with conventional cardiac arrest team-based responses to emergencies (control). We examined emergency calls in all hospitals. In intervention hospitals, we also examined such calls in the period before, during the introduction, and after the full implementation of a rapid response system. We studied the statistical association between such delayed calls and mortality.Main Outcomes and Measures: Hospital outcomes (mortality, unplanned ICU admissions, and cardiac arrests).Results: There were 3,135 emergency team calls in all hospitals. Overall, almost one third of such calls were delayed. In intervention hospitals, the proportion of delayed calls was similar before and after implementation of rapid response teams. Compared with control hospitals, in intervention hospitals, there was a significant decrease in the proportion of delayed calls during both the introduction (27.3% vs 34.3% weekly rate; incidence rate ratio, 0.84; p = 0.001) and the full implementation period (29.0% vs 34.5% weekly rate; incidence rate ratio, 0.84; p = 0.023). Delayed calls more likely occurred at night, in high dependence or coronary care units, in patients older than 75 years, in those with a decrease in Glasgow Coma Scale, or in those with hypotension as the reason for the call. Finally, in all hospitals, delayed calls were associated with an increased risk of unplanned ICU admissions (adjusted odds ratio = 1.56; 95% CI, 1.23-2.04; p ≤ 0.001) and death (adjusted odds ratio = 1.79; 95% CI, 1.43-2.27; p < 0.001).Conclusions: Among ward patients, emergency team activation in response to acute deterioration triggered more than 15 minutes after detection and documentation of instability is independently associated with an increased risk of ICU admission and death. [ABSTRACT FROM AUTHOR]

The authors highlight the side effects of hydroxyethyl starch (HES), an artificial colloid solution used in treating hypovolemia. Topics covered include link of HES in the increased risk of acute kidney injury (AKI), trials showing increased risk of bleeding with the use of HES as compared with crystalloid solutions in patients with sepsis, and increased mortality with HES in critically ill patients.

Aim While patients with chronic kidney disease have reduced health-related quality of life ( HRQOL), long-term HRQOL of survivors of severe acute kidney injury ( AKI) remains unclear. Methods We analysed HRQOL from the Prolonged Outcomes Study of the Randomized Evaluation of Normal versus Augmented Level Replacement Therapy ( POST-RENAL) study and compared findings with those from a general Australian adult population enrolled in the Australian Diabetes, Obesity and Lifestyle ( Aus Diab) study. We used a multivariate analysis adjusted for baseline characteristics along with sensitivity analysis using age and sex-matched case controls. Results In the POST-RENAL study, 282 participants had HRQOL data collected using the SF-12 questionnaire. This was compared with 6330 participants from the Aus Diab study. Unadjusted analyses showed that POST-RENAL participants had lower physical component scores ( PCS, mean score 40.0 vs 49.8, P < 0.0001) and lower mental component scores ( MCS, mean score 49.8 vs 53.9, P < 0.0001) than the Aus Diab group. After age and sex matching, the difference in PCS and MCS remained statistically significant ( P < 0.0001). Advanced age, reduced renal function and albuminuria (all P ≤ 0.01) were all strongly associated with lower PCS values but not MCS values. After matching subsets of the cohorts on the basis of age, sex and renal function, PCS and MCS were lower in the POST-RENAL group ( P < 0.0001). Conclusion Survivors of severe AKI in the POST-RENAL study had lower physical and mental components of HRQOL compared with general population, even after adjustment for their reduced renal function. Increasing age and reduced renal function were associated with poorer physical QOL. [ABSTRACT FROM AUTHOR]

Purpose: In a previous study, restricting intravenous chloride administration in ICU patients decreased the incidence of acute kidney injury (AKI). To test the robustness of this finding, we extended our observation period to 12 months. Methods: The study extension included a 1-year control period (18 August 2007 to 17 August 2008) and a 1-year intervention period (18 February 2009 to 17 February 2010). During the extended control period, patients received standard intravenous fluids. During the extended intervention period, we continued to restrict all chloride-rich fluids. We used the Kidney Disease: Improving Global Outcomes (KDIGO) staging to define AKI. Results: We studied 1,476 control and 1,518 intervention patients. Stages 2 and 3 of KDIGO defined AKI decreased from 302 (20.5 %; 95 % CI, 18.5-22.6 %) to 238 (15.7 %; 95 % CI, 13.9-17.6 %) ( P < 0.001) and the use of RRT from 144 (9.8 %; 95 % CI, 8.3-11.4 %) to 103 (6.8 %; 95 % CI, 5.6-8.2 %) ( P = 0.003). After adjustment for relevant covariates, liberal chloride therapy remained associated with a greater risk of KDIGO stages 2 and 3 [hazard ratio 1.32 (95 % CI 1.11-1.58); P = 0.002] and use of RRT [hazard ratio 1.44 (95 % CI 1.10-1.88); P = 0.006]. However, on sensitivity assessment of each 6-month period, KDIGO stages 2 and 3 increased in the new extended intervention period compared with the original intervention period. Conclusions: On extended assessment, the overall impact of restricting chloride-rich fluids on AKI remained. However, sensitivity analysis suggested that other unidentified confounders may have also contributed to fluctuations in the incidence of AKI. [ABSTRACT FROM AUTHOR]

For many years, neutrophil gelatinase-associated lipocalin (NGAL) has been considered the most promising biomarker of acute kidney injury (AKI). Commercial assays and point-of-care instruments, now available in many hospitals, allow rapid NGAL measurements intended to guide the clinician in the management of patients with or at risk of AKI. However, these assays likely measure a mixture of different NGAL forms originating from different tissues. Systemic inflammation, commonly seen in critically ill patients, and several comorbidities contribute to the release of NGAL from haematopoietic and non-haematopoietic cells. The unpredictable release and complex nature of the molecule and the inability to specifically measure NGAL released by tubular cells have hampered its use a specific marker of AKI in heterogeneous critically ill populations. In this review, we describe the nature and cellular sources of NGAL, its biological role and diagnostic ability in AKI and the increasing concerns surrounding its diagnostic and clinical value. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and Aims: We aimed to examine the association between dailyprotein intake (DPI) and outcomes in patients from the Randomized Evaluation of Normal versus Augmented Level (RENAL) trial. Methods: We analyzed the association between DPI and clinical outcomes using multivariable logistic regression, Cox proportional hazards models and time-adjusted analysis. Results: During ICU stay, mean DPI was 37.6 g/day among survivors and 37.7 g/day among nonsurvivors (p = 0.96; DPI of 0.5 g/kg/day). Only 159 (10.9%) of the patients received a mean DPI of >1 g/kg. Patients with a DPI above the median had a 43.1% mortality compared with 46.1% for a DPI below the median (p = 0.25). On multivariate analysis, a lower DPI was not associated with increased odds ratios for 90-day mortality or any secondary outcomes. Cox proportional hazards models and time-adjusted analysis confirmed these findings. Conclusions: In the RENAL study, mean DPI was low. Within the confines of such low DPI, greater amounts of DPI were not independently associated with improved clinical outcomes. Video Journal Club 'Cappuccino with Claudio Ronco' at www.karger.com/?doi=363175. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim Acute kidney injury ( AKI) is associated with increased mortality. While angiotensin-converting enzyme inhibitors ( ACEI) are known to slow progression of chronic kidney disease, their role in AKI remains unclear. Methods The Randomised Evaluation of Normal vs. Augmented Level Replacement Therapy ( RENAL) study data were analysed according to ACEI use over time. The primary outcome was all-cause mortality at 90 days following randomisation. Analyses used a multivariate Cox model adjusted for either baseline or for time-dependent covariates, and a sensitivity analysis of patients surviving to at least the median time to ACEI initiation. Results Of the 1463 participants with available data on ACE inhibitors usage, 142 (9.7%) received ACEI at least once during study data collection. Participants treated with ACEI were older ( P = 0.02) and had less sepsis at baseline ( P < 0.001). ACEI use was significantly associated with lower mortality at 90 days ( HR 0.46, 95% CI 0.30-0.71, P < 0.001), and an increase in renal replacement therapy-free days ( P < 0.001), intensive care unit-free days ( P < 0.001) and hospital free-days ( P < 0.001) after adjusting for baseline covariates. Using the time-dependent analysis, however, the effect of ACEI administration was not significant ( HR 0.78, 95% CI 0.51-1.21, P = 0.3). The sensitivity analysis in day 8 survivors produced similar results. Conclusion In the RENAL study cohort, the use of ACEI during the study was not common and, after adjustment for time-dependent covariates, was not significantly associated with reductions in mortality. Further assessment of the effect of ACEI use in AKI patients is needed. [ABSTRACT FROM AUTHOR]

Objectives: To explore the relationship between timing of continuous renal replacement therapy commencement and clinical outcomes in critically ill patients with acute kidney injury. The primary outcomes were all-cause mortality at 28 and 90 days. Design: Nested observational cohort study using data from the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study. Setting: Twenty-three ICUs in Australia and New Zealand. Patients: Four hundred thirty-nine critically ill patients with acute kidney injury Risk, Injury, Failure, Loss, End-stage kidney disease-injury (RIFLE-I) criteria. Interventions: None. Measurements and Main Results: The time between RIFLE-I acute kidney injury and randomization in the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study (proxy for continuous renal replacement therapy commencement) was the variable of interest. All baseline variables in the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study were assessed. Multivariable Cox, logistic, and linear regression models were used to assess the independent relationship of time of onset of RIFLE-I acute kidney injury and randomization and patient outcomes. The median time between RIFLE-I acute kidney injury and continuous renal replacement therapy commencement was 17.6 hours (interquartile range, 7.1-46 hr). Based on four groups of continuous renal replacement therapy commencement ([group 1; reference]: <7.1, [group 2]: ⩾ 7.1 to < 17.6, [group 3]: ⩾ 17.6 to < 46.0, [group 4]: ⩾ 46.0hr), earlier commencement of continuous renal replacement therapy was not associated with a significantly lower risk of death at 28 days (hazard ratio for group 2: 1.06, 95% Cl: 0.62-1.81; p = 0.83; hazard ratio for group 3: 1.23, 95% Cl: 0.71-2.12; p = 0.46; hazard ratio for group 4: 1.33, 95% Cl: 0.77- 2.31 ;p = 0.31). Similar findings were observed for death at 90 days. Conclusions: In a subgroup of participants of the Randomized Evaluation of Normal Versus Augmented Level Replacement Therapy Study, earlier commencement of continuous renal replacement therapy relative to RIFLE-I acute kidney injury was not significantly associated with improved survival. Additional studies with larger sample sizes and broader commencement times are warranted. [ABSTRACT FROM AUTHOR]