Assessing the role of Chemokine (C-C motif) ligand 14 in AKI: a European consensus meeting.

BACKGROUND: Urinary Chemokine (C-C motif) ligand 14 (CCL14) is a biomarker associated with persistent severe acute kidney injury (AKI). There is limited data to support the implementation of this AKI biomarker to guide therapeutic actions. METHODS: Sixteen AKI experts with clinical CCL14 experience participated in a Delphi-based method to reach consensus on when and how to potentially use CCL14. Consensus was defined as ≥ 80% agreement (participants answered with 'Yes', or three to four points on a five-point Likert Scale). RESULTS: Key consensus areas for CCL14 test implementation were: identifying challenges and mitigations, developing a comprehensive protocol and pairing it with a treatment plan, and defining the target population. The majority agreed that CCL14 results can help to prioritize AKI management decisions. CCL14 levels above the high cutoff (> 13 ng/mL) significantly changed the level of concern for modifying the AKI treatment plan (p < 0.001). The highest level of concern to modify the treatment plan was for discussions on renal replacement therapy (RRT) initiation for CCL14 levels > 13 ng/mL. The level of concern for discussion on RRT initiation between High and Low, and between Medium and Low CCL14 levels, showed significant differences. CONCLUSION: Real world urinary CCL14 use appears to provide improved care options to patients at risk for persistent severe AKI. Experts believe there is a role for CCL14 in AKI management and it may potentially reduce AKI-disease burden. There is, however, an urgent need for evidence on treatment decisions and adjustments based on CCL14 results.

Hemoadsorption: Consensus report of the 30th Acute Disease Quality Initiative workgroup.

Adsorption-based extracorporeal therapies have been subject to technical developments and clinical application for close to five decades. More recently, new technological developments in membrane and sorbent manipulation have made it possible to deliver more biocompatible extracorporeal adsorption therapies to patients with a variety of conditions. There are several key rationales based on physicochemical principles and clinical considerations that justify the application and investigation of such therapies as evidenced by multiple ex-vivo, experimental, and clinical observations. Accordingly, unspecific adsorptive extracorporeal therapies have now been applied to the treatment of a wide array of conditions from poisoning to drug overdoses, to inflammatory states and sepsis, and acute or chronic liver and kidney failure. In response to the rapidly expanding knowledge base and increased clinical evidence, we convened an Acute Disease Quality Initiative (ADQI) consensus conference dedicated to such treatment. The data show that hemoadsorption has clinically acceptable short-term biocompatibility and safety, technical feasibility, and experimental demonstration of specified target molecule removal. Pilot studies demonstrate potentially beneficial effects on physiology and larger studies of endotoxin-based hemoadsorption have identified possible target phenotypes for larger randomized controlled trials (RCTs). Moreover, in a variety of endogenous and exogenous intoxications, removal of target molecules has been confirmed in vivo. However, some studies have raised concerns about harm or failed to deliver benefits. Thus, despite many achievements, modern hemoadsorption remains a novel and experimental intervention with limited data, and a large research agenda.

CCL14 testing to guide clinical practice in patients with AKI: Results from an international expert panel.

PURPOSE: Urinary C-C motif chemokine ligand 14 (CCL14) is a strong predictor of persistent stage 3 acute kidney injury (AKI). Multiple clinical actions are recommended for AKI but how these are applied in individual patients and how the CCL14 test results may impact their application is unknown. METHODS: We assembled an international panel of 12 experts and conducted a modified Delphi process to evaluate patients at risk for persistent stage 3 AKI (lasting 72 hours or longer). Using a Likert scale, we rated 11 clinical actions based on international guidelines applied to each case before and after CCL14 testing and analyzed the association between the strength and direction of recommendations and CCL14 results. RESULTS: The strength and direction of clinical recommendations were strongly influenced by CCL14 results (P < 0.001 for the interaction). Nine (82%) recommendations for clinical actions were significantly impacted by CCL14 results (P < 0.001 comparing low to highest CCL14 risk category). CONCLUSIONS: Most recommendations for care of patients with stage 2-3 by an international panel of experts were strongly modified by CCL14 test results. This work should set the stage for clinical practice protocols and studies to determine the effects of recommended actions informed by CCL14.

Creatine supplementation for optimization of physical function in the patient at risk of functional disability: A systematic review and meta-analysis.

BACKGROUND: The efficacy of creatine replacement through supplementation for the optimization of physical function in the population at risk of functional disability is unclear. METHODS: We conducted a systematic literature search of MEDLINE, EMBASE, the Cochrane Library, and CINAHL from inception to November 2022. Studies included were randomized controlled trials (RCTs) comparing creatine supplementation with placebos in older adults and adults with chronic disease. The primary outcome was physical function measured by the sit-to-stand test after pooling data using random-effects modeling. We also performed a Bayesian meta-analysis to describe the treatment effect in probability terms. Secondary outcomes included other measures of physical function, muscle function, and body composition. The risk of bias was assessed using the Cochrane risk-of-bias tool. RESULTS: We identified 33 RCTs, comprising 1076 participants. From six trials reporting the primary outcome, the pooled standardized mean difference (SMD) was 0.51 (95% confidence interval [CI]: 0.01-1.00; I2 = 62%; P = 0.04); using weakly informative priors, the posterior probability that creatine supplementation improves physical function was 66.7%. Upper-body muscle strength (SMD: 0.25; 95% CI: 0.06-0.44; I2 = 0%; P = 0.01), handgrip strength (SMD 0.23; 95% CI: 0.01-0.45; I2 = 0%; P = 0.04), and lean tissue mass (MD 1.08 kg; 95% CI: 0.77-1.38; I2 = 26%; P < 0.01) improved with creatine supplementation. The quality of evidence for all outcomes was low or very low because of a high risk of bias. CONCLUSION: Creatine supplementation improves sit-to-stand performance, muscle function, and lean tissue mass. It is crucial to conduct high-quality prospective RCTs to confirm these hypotheses (PROSPERO number, CRD42023354929).

Association between urea trajectory and protein dose in critically ill adults: a secondary exploratory analysis of the effort protein trial (RE-EFFORT).

BACKGROUND: Delivering higher doses of protein to mechanically ventilated critically ill patients did not improve patient outcomes and may have caused harm. Longitudinal urea measurements could provide additional information about the treatment effect of higher protein doses. We hypothesised that higher urea values over time could explain the potential harmful treatment effects of higher doses of protein. METHODS: We conducted a reanalysis of a randomised controlled trial of higher protein doses in critical illness (EFFORT Protein). We applied Bayesian joint models to estimate the strength of association of urea with 30-day survival and understand the treatment effect of higher protein doses. RESULTS: Of the 1301 patients included in EFFORT Protein, 1277 were included in this analysis. There were 344 deaths at 30 days post-randomisation. By day 6, median urea was 2.1 mmol/L higher in the high protein group (95% CI 1.1-3.2), increasing to 3.0 mmol/L (95% CI 1.3-4.7) by day 12. A twofold rise in urea was associated with an increased risk of death at 30 days (hazard ratio 1.34, 95% credible interval 1.21-1.48), following adjustment of baseline characteristics including age, illness severity, renal replacement therapy, and presence of AKI. This association persisted over the duration of 30-day follow-up and in models adjusting for evolution of organ failure over time. CONCLUSIONS: The increased risk of death in patients randomised to a higher protein dose in the EFFORT Protein trial was estimated to be mediated by increased urea cycle activity, of which serum urea is a biological signature. Serum urea should be taken into consideration when initiating and continuing protein delivery in critically ill patients. CLINICALTRIALS: gov Identifier: NCT03160547 (2017-05-17).

Cystatin C or creatinine for pre-operative assessment of kidney function and risk of post-operative acute kidney injury: a secondary analysis of the METS cohort study.

Background: Post-operative acute kidney injury (PO-AKI) is a common surgical complication consistently associated with subsequent morbidity and mortality. Prior kidney dysfunction is a major risk factor for PO-AKI, however it is unclear whether serum creatinine, the conventional kidney function marker, is optimal in this population. Serum cystatin C is a kidney function marker less affected by body composition and might provide better prognostic information in surgical patients. Methods: This was a pre-defined, secondary analysis of a multi-centre prospective cohort study of pre-operative functional capacity. Participants were aged ≥40 years, undergoing non-cardiac surgery. We assessed the association of pre-operative estimated glomerular filtration rate (eGFR) calculated using both serum creatinine and serum cystatin C with PO-AKI within 3 days after surgery, defined by KDIGO creatinine changes. The adjusted analysis accounted for established AKI risk factors. Results: A total of 1347 participants were included (median age 65 years, interquartile range 56-71), of whom 775 (58%) were male. A total of 82/1347 (6%) patients developed PO-AKI. These patients were older, had higher prevalence of cardiovascular disease and related medication, were more likely to have intra-abdominal procedures, had more intraoperative transfusion, and were more likely to be dead at 1 year after surgery 6/82 (7.3%) vs 33/1265 (2.7%) (P = .038). Pre-operative eGFR was lower in AKI than non-AKI patients using both creatinine and cystatin C. When both measurements were considered in a single age- and sex-adjusted model, eGFR-Cysc was strongly associated with PO-AKI, with increasing risk of AKI as eGFR-Cysc decreased below 90, while eGFR-Cr was no longer significantly associated. Conclusions: Data from over 1000 prospectively recruited surgical patients confirms pre-operative kidney function as major risk factor for PO-AKI. Of the kidney function markers available, compared with creatinine, cystatin C had greater strength of association with PO-AKI and merits further assessment in pre-operative assessment of surgical risk.

Association between energy surplus and intensive care unit length of stay in critically ill patients: A retrospective cohort study.

BACKGROUND: Patients experiencing persistent critical illness have poor short-term and long-term outcomes and consume disproportionate amounts of health care resources. Nutrition optimization may improve outcomes, though few data exist on resting energy expenditure and nutrition requirements. We hypothesized that increased energy surplus per day is associated with increased intensive care unit (ICU) length of stay (LoS) in critically ill patients. METHODS: Patients from a single ICU at Royal London Hospital were included in this retrospective cohort study. EXPOSURE: energy surplus measured by serial indirect calorimetry (IC) and nutrition intake. INCLUSION CRITERIA: mechanical ventilation of ≥3 days and expected to remain ventilated. PRIMARY OUTCOME: ICU LoS. RESULTS: Across 30 patients (median LoS 21 days), increased ICU LoS was associated with actual daily energy intake surplus to resting energy expenditure (REE) (R2 0.16; P < 0.005). Median REE was less than predicted energy requirements: 24 kcal per day per kilogram of ideal body weight (IBW) (interquartile range [IQR], 20-28) vs 28 kcal/day/kg IBW (IQR, 26-29) (P < 0.001). Patients with COVID-19 had a median energy surplus (actual intake- REE) + 344 kcal/day (IQR 35-517) vs -57 kcal/day (IQR -324 to 211) in other patients (P = 0.011); however, they had a median LoS of 44 days (IQR 26-58) vs 10 days (IQR 7-24), respectively (P < 0.001). Patients with obesity had a median energy deficit of -32 kcal/day (IQR -384 to 335) vs +234 kcal/day (IQR -79 to 499) for nonobese patients (P = 0.021). CONCLUSION: Overfeeding represents an easily modifiable factor to improve outcomes in patients experiencing persistent critical illness, for which IC may be useful.

Supporting effective shared decision-making in surgical context: Why framing of choices matters for high-risk patients and clinicians.

AIM: In the context of high-risk surgery, shared decision-making (SDM) is important. However, the effectiveness of SDM can be hindered by misalignment between patients and clinicians in their expectations of postoperative outcomes. This study investigated the extent and the effects of this misalignment, as well as its amenability to interventions that encourage perspective-taking. METHOD: Lay participants with a Charlson Comorbidity Index of ≥4 (representing patients) and surgeons and anaesthetists (representing doctors) were recruited. During an online experiment, subjects in both groups forecast their expectations regarding short-term (0, 1 and 3 months after treatment) and long-term (6, 9 and 12 months after treatment) outcomes of different treatment options for one of three hypothetical clinical scenarios - ischaemic heart disease, colorectal cancer or osteoarthritis of the hip - and then chose between surgical or non-surgical treatment. Subjects in both groups were asked to consider the scenarios from their own perspective (Estimation task), and then to adopt the perspective of subjects in the other study group (Perspective task). The decisions of all participants (surgery vs. non-surgical alternative) were analysed using binomial generalized linear mixed models. RESULTS: In total, 55 lay participants and 54 doctors completed the online experiment. Systematic misalignment in expectations between high-risk patients and doctors was observed, with patients expecting better surgical outcomes than clinicians. Patients forecast a significantly higher likelihood of engaging in normal activities in the long term (ß = -1.09, standard error [SE] = 0.20, t = -5.38, p < 0.001), a lower likelihood of experiencing complications in the long term (ß = 0.92, SE = 0.21, t = 4.45, p < 0.001) and a lower likelihood of experiencing depression in both the short term and the long term (ß = 1.01, SE = 0.19, t = 5.38, p < 0.001), than did doctors. Compared with doctors, patients forecast higher estimates of experiencing complications in the short term when a non-surgical alternative was selected (ß = -0.91, SE = 0.26, t = -3.50, p = 0.003). Despite this misalignment, in both groups surgical treatment was strongly preferred (estimation task: 88.7% of doctors and 80% of patients; perspective task: 82.2% of doctors and 90.1% of patients). CONCLUSION: When high-risk surgery is discussed, a non-surgical option may be viewed as 'doing nothing', hence reducing the sense of agency and control. This biases the decision-making process, regardless of the expectations that doctors and patients might have about the outcomes of surgery. Therefore, to improve SDM and to increase the agency and control of patients regarding decisions about their care, we advocate framing the non-surgical treatment options in a way that emphasizes action, agency and change.

Nomenclature of Extracorporeal Blood Purification Therapies for Acute Indications: The Nomenclature Standardization Conference.

The development of new extracorporeal blood purification (EBP) techniques has led to increased application in clinical practice but also inconsistencies in nomenclature and misunderstanding. In November 2022, an international consensus conference was held to establish consensus on the terminology of EBP therapies. It was agreed to define EBP therapies as techniques that use an extracorporeal circuit to remove and/or modulate circulating substances to achieve physiological homeostasis, including support of the function of specific organs and/or detoxification. Specific acute EBP techniques include renal replacement therapy, isolated ultrafiltration, hemoadsorption, and plasma therapies, all of which can be applied in isolation and combination. This paper summarizes the proposed nomenclature of EBP therapies and serves as a framework for clinical practice and future research.

A pilot study of alternative substrates in the critically Ill subject using a ketogenic feed.

Bioenergetic failure caused by impaired utilisation of glucose and fatty acids contributes to organ dysfunction across multiple tissues in critical illness. Ketone bodies may form an alternative substrate source, but the feasibility and safety of inducing a ketogenic state in physiologically unstable patients is not known. Twenty-nine mechanically ventilated adults with multi-organ failure managed on intensive care units were randomised (Ketogenic n = 14, Control n = 15) into a two-centre pilot open-label trial of ketogenic versus standard enteral feeding. The primary endpoints were assessment of feasibility and safety, recruitment and retention rates and achievement of ketosis and glucose control. Ketogenic feeding was feasible, safe, well tolerated and resulted in ketosis in all patients in the intervention group, with a refusal rate of 4.1% and 82.8% retention. Patients who received ketogenic feeding had fewer hypoglycaemic events (0.0% vs. 1.6%), required less exogenous international units of insulin (0 (Interquartile range 0-16) vs.78 (Interquartile range 0-412) but had slightly more daily episodes of diarrhoea (53.5% vs. 42.9%) over the trial period. Ketogenic feeding was feasible and may be an intervention for addressing bioenergetic failure in critically ill patients. Clinical Trials.gov registration: NCT04101071.

Hypoxemia Trajectory of Non-COVID-19 Acute Respiratory Distress Syndrome Patients. An Observational Study Focusing on Hypoxemia Resolver Status.

IMPORTANCE: Most studies on acute respiratory distress syndrome (ARDS) group patients by severity based on their initial degree of hypoxemia. However, this grouping has limitations, including inconsistent hypoxemia trajectories and outcomes. OBJECTIVES: This study explores the benefits of grouping patients by resolver status based on their hypoxemia progression over the first 7 days. DESIGN SETTING AND PARTICIPANTS: This is an observational study from a large single-center database. Medical Information Mart for Intensive Care (MIMIC)-IV and MIMIC Chest X-ray JPEG databases were used. Mechanically ventilated patients that met the Berlin ARDS criteria were included. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of hypoxemia resolvers vs. nonresolvers in non-COVID-19 ARDS patients. Nonresolvers were defined as those whose hypoxemia worsened or remained moderate or severe over the first 7 days. Secondary outcomes included baseline admission characteristics, initial blood gases and ventilation settings, length of invasive mechanical ventilation, length of ICU stay, and ICU survival rates across resolver groups. RESULTS: A total of 894 ICU admissions were included in the study. Of these, 33.9% were hypoxemia nonresolvers. The resolver groups showed no significant difference in age, body mass index, comorbidities, or Charlson score. There was no significant difference in the percentage of those with initial severe hypoxemia between the two groups (8.1% vs. 9.2%; p = 0.126). The initial Pao2/Fio2 ratio did not significantly increase the odds ratio (OR) of being a nonresolver (OR, 0.84; 95% CI, 0.65-1.10). Nonresolver mortality was 61.4%, comparable to the survival rates seen in nonresolvers in a previous large COVID-19 ARDS study. CONCLUSIONS AND RELEVANCE: Our study shows that resolver status is a valuable grouping in ARDS. It has significant advantages over grouping by initial degree of hypoxemia, including better mapping of trajectory and comparable outcomes across other studies. While it may offer insights into disease-specific associations, future studies should include resolver status analysis for more definitive conclusions.

Long-term healthcare use after postoperative complications: an analysis of linked primary and secondary care routine data.

Background: Postoperative complications are associated with reduced long-term survival. We characterise healthcare use changes after sentinel postoperative complications. Methods: We linked primary and secondary care records of patients undergoing elective surgery at four East London hospitals (2012-7) with at least 90 days follow-up. Complication codes (wound infection, urinary tract infection, pneumonia, new stroke, and new myocardial infarction) recorded within 90 days of surgery were identified from primary or secondary care. Outcomes were change in healthcare contact days in the 2 yr before and after surgery, and 2 yr mortality. We report rate ratios (RaR) with 95% confidence intervals and adjusted for baseline healthcare use and confounders using negative binomial regression. Results: We included 49 913 patients (median age 49 yr [inter-quartile range {IQR}: 34-64]), 27 958 (56.0%) were female. Amongst 3883 (7.8%) patients with complications (median age 58 [IQR: 43-72]), there were 18.4 days per year in contact with healthcare before surgery and 25.3 days after surgery (RaR: 1.38 [1.37-1.39]). Patients without complications (median age 48 [IQR: 33-63]) had 12.3 days per year in contact with healthcare before surgery and 14.0 days after surgery (RaR: 1.14 [1.14-1.15]). The adjusted incidence rate ratio of days in contact with healthcare associated with complications was 1.67 (1.49-1.87). More patients (391; 10.1%) with complications died within 2 yr than those without (1428; 3.1%). Conclusions: Patients with postoperative complications are older with greater healthcare use before surgery. However, their absolute and relative increases in healthcare use after surgery are greater than patients without complications.

Long-term disease interactions amongst surgical patients: a population cohort study.

BACKGROUND: The average age of the surgical population continues to increase, as does prevalence of long-term diseases. However, outcomes amongst multi-morbid surgical patients are not well described. METHODS: We included adults undergoing non-obstetric surgical procedures in the English National Health Service between January 2010 and December 2015. Patients could be included multiple times in sequential 90-day procedure spells. Multi-morbidity was defined as presence of two or more long-term diseases identified using a modified Charlson comorbidity index. The primary outcome was 90-day postoperative death. Secondary outcomes included emergency hospital readmission within 90 days. We calculated age- and sex-adjusted odds ratios (OR) with 95% confidence intervals (CI) using logistic regression. We compared the outcomes associated with different disease combinations. RESULTS: We identified 20 193 659 procedure spells among 13 062 715 individuals aged 57 (standard deviation 19) yr. Multi-morbidity was present among 2 577 049 (12.8%) spells with 195 965 deaths (7.6%), compared with 17 616 610 (88.2%) spells without multi-morbidity with 163 529 deaths (0.9%). Multi-morbidity was present in 1 902 859/16 946 808 (11.2%) elective spells, with 57 663 deaths (2.7%, OR 4.9 [95% CI: 4.9-4.9]), and 674 190/3 246 851 (20.7%) non-elective spells, with 138 302 deaths (20.5%, OR 3.0 [95% CI: 3.0-3.1]). Emergency readmission followed 547 399 (22.0%) spells with multi-morbidity compared with 1 255 526 (7.2%) without. Multi-morbid patients accounted for 57 663/114 783 (50.2%) deaths after elective spells, and 138 302/244 711 (56.5%) after non-elective spells. The rate of death varied five-fold from lowest to highest risk disease pairs. CONCLUSION: One in eight patients undergoing surgery have multi-morbidity, accounting for more than half of all postoperative deaths. Disease interactions amongst multi-morbid patients is an important determinant of patient outcome.

Hemoperfusion in Trauma.

Major trauma care has seen significant improvements in early mortality, reflecting improvements in prehospital techniques for hemorrhage control and speed of access to specialized trauma centers. However, many patients then go on to die in the intensive care unit (ICU), and improvements in immediate trauma care are presenting intensivists with greater numbers of severely injured patients who might previously have died shortly after injury. It is theorized that, despite initial survival, these patients deteriorate due to massive release of damage associated molecular patterns (DAMPs) after traumatic and ischemic tissue injury. These trigger a vicious cycle of overactive pro- and anti-inflammatory pathways, leading to organ dysfunction and immunoparesis. Extracorporeal hemoperfusion, with its ability to adsorb both DAMPs and inflammatory mediators from the bloodstream, has the potential to break this cycle and could, in theory, then prevent early death or organ dysfunction in the ICU. However, currently, there has been little research around the indications for, and efficacy of, this therapy in the setting of polytrauma. Here we outline potential molecular targets, summarize existing exploratory studies, and suggest areas for future research required to establish the benefits of hemoperfusion as an adjunct therapy in major polytrauma.

Characterising biological mechanisms underlying ethnicity-associated outcomes in COVID-19 through biomarker trajectories: a multicentre registry analysis.

BACKGROUND: Differences in routinely collected biomarkers between ethnic groups could reflect dysregulated host responses to disease and to treatments, and be associated with excess morbidity and mortality in COVID-19. METHODS: A multicentre registry analysis from patients aged ≥16 yr with SARS-CoV-2 infection and emergency admission to Barts Health NHS Trust hospitals during January 1, 2020 to May 13, 2020 (wave 1) and September 1, 2020 to February 17, 2021 (wave 2) was subjected to unsupervised longitudinal clustering techniques to identify distinct phenotypic patient clusters based on trajectories of routine blood results over the first 15 days of hospital admission. Distribution of trajectory clusters across ethnic categories was determined, and associations between ethnicity, trajectory clusters, and 30-day survival were assessed using multivariable Cox proportional hazards modelling. Secondary outcomes were ICU admission, survival to hospital discharge, and long-term survival to 640 days. RESULTS: We included 3237 patients with hospital length of stay ≥7 days. In patients who died, there was greater representation of Black and Asian ethnicity in trajectory clusters for C-reactive protein and urea-to-creatinine ratio associated with increased risk of death. Inclusion of trajectory clusters in survival analyses attenuated or abrogated the higher risk of death in Asian and Black patients. Inclusion of C-reactive protein went from hazard ratio (HR) 1.36 [0.95-1.94] to HR 0.97 [0.59-1.59] (wave 1), and from HR 1.42 [1.15-1.75]) to HR 1.04 [0.78-1.39] (wave 2) in Asian patients. Trajectory clusters associated with reduced 30-day survival were similarly associated with worse secondary outcomes. CONCLUSIONS: Clinical biochemical monitoring of COVID-19 and progression and treatment response in SARS-CoV-2 infection should be interpreted in the context of ethnic background.

Comparison of Cystatin C and Creatinine in the Assessment of Measured Kidney Function during Critical Illness.

BACKGROUND: Incomplete recovery of kidney function is an important adverse outcome in survivors of critical illness. However, unlike eGFR creatinine, eGFR cystatin C is not confounded by muscle loss and may improve identification of persistent kidney dysfunction. METHODS: To assess kidney function during prolonged critical illness, we enrolled 38 mechanically ventilated patients with an expected length of stay of >72 hours near admission to intensive care unit (ICU) in a single academic medical center. We assessed sequential kidney function using creatinine, cystatin C, and iohexol clearance measurements. The primary outcome was difference between eGFR creatinine and eGFR cystatin C at ICU discharge using Bayesian regression modeling. We simultaneously measured muscle mass by ultrasound of the rectus femoris to assess the confounding effect on serum creatinine generation. RESULTS: Longer length of ICU stay was associated with greater difference between eGFR creatinine and eGFR cystatin C at a predicted rate of 2 ml/min per 1.73 m 2 per day (95% confidence interval [CI], 1 to 2). By ICU discharge, the posterior mean difference between creatinine and cystatin C eGFR was 33 ml/min per 1.73 m 2 (95% credible interval [CrI], 24 to 42). In 27 patients with iohexol clearance measured close to ICU discharge, eGFR creatinine was on average two-fold greater than the iohexol gold standard, and posterior mean difference was 59 ml/min per 1.73 m 2 (95% CrI, 49 to 69). The posterior mean for eGFR cystatin C suggested a 22 ml/min per 1.73 m 2 (95% CrI, 13 to 31) overestimation of measured GFR. Each day in ICU resulted in a predicted 2% (95% CI, 1% to 3%) decrease in muscle area. Change in creatinine-to-cystatin C ratio showed good longitudinal, repeated measures correlation with muscle loss, R =0.61 (95% CI, 0.50 to 0.72). CONCLUSIONS: eGFR creatinine systematically overestimated kidney function after prolonged critical illness. Cystatin C better estimated true kidney function because it seemed unaffected by the muscle loss from prolonged critical illness. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Skeletal Muscle Wasting and Renal Dysfunction After Critical Illness Trauma - Outcomes Study (KRATOS), NCT03736005 .

Serial Urinary C-C Motif Chemokine Ligand 14 and Risk of Persistent Severe Acute Kidney Injury.

To assess the added prognostic value of serial monitoring of urinary C-C motif chemokine ligand 14 (uCCL14) over that of single measurements, which have been shown to be prognostic for development of persistent severe acute kidney injury (AKI) in critically ill patients. DESIGN: Retrospective observational study. SETTING: Data derived from two multinational ICU studies (Ruby and Sapphire). PATIENTS: Critically ill patients with early stage 2-3 AKI. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed three consecutive uCCL14 measurements at 12-hour intervals after diagnosis of stage 2-3 AKI by Kidney Disease Improving Global Outcomes criteria. Primary outcome was persistent severe AKI, defined as 72 consecutive hours of stage 3 AKI, death, or receipt of dialysis prior to 72 hours. uCCL14 was measured using the NEPHROCLEAR uCCL14 Test on the Astute 140 Meter (Astute Medical, San Diego, CA). Based on predefined, validated cutoffs, we categorized uCCL14 as: low (≤ 1.3 ng/mL), medium (> 1.3 to ≤ 13 ng/mL), or high (> 13 ng/mL). Seventy-five of 417 patients with three consecutive uCCL14 measurements developed persistent severe AKI. Initial uCCL14 category strongly correlated with primary endpoint and, in most cases (66%), uCCL14 category was unchanged over the first 24 hours. Compared with no change and accounting for baseline category, decrease in category was associated with decreased odds of persistent severe AKI (odds ratio [OR], 0.20; 95% CI, 0.08-0.45; p < 0.001) and an increase in category with increased odds (OR, 4.04; 95% CI, 1.75-9.46; p = 0.001). CONCLUSIONS: In one-third of patients with moderate to severe AKI uCCL14 risk category altered over three serial measurements and such changes were associated with altered risk for persistent severe AKI. Serial CCL-14 measurement may detect progression or resolution of underlying kidney pathology and help refine AKI prognosis.

Sepsis-associated acute kidney injury: consensus report of the 28th Acute Disease Quality Initiative workgroup.

Sepsis-associated acute kidney injury (SA-AKI) is common in critically ill patients and is strongly associated with adverse outcomes, including an increased risk of chronic kidney disease, cardiovascular events and death. The pathophysiology of SA-AKI remains elusive, although microcirculatory dysfunction, cellular metabolic reprogramming and dysregulated inflammatory responses have been implicated in preclinical studies. SA-AKI is best defined as the occurrence of AKI within 7 days of sepsis onset (diagnosed according to Kidney Disease Improving Global Outcome criteria and Sepsis 3 criteria, respectively). Improving outcomes in SA-AKI is challenging, as patients can present with either clinical or subclinical AKI. Early identification of patients at risk of AKI, or at risk of progressing to severe and/or persistent AKI, is crucial to the timely initiation of adequate supportive measures, including limiting further insults to the kidney. Accordingly, the discovery of biomarkers associated with AKI that can aid in early diagnosis is an area of intensive investigation. Additionally, high-quality evidence on best-practice care of patients with AKI, sepsis and SA-AKI has continued to accrue. Although specific therapeutic options are limited, several clinical trials have evaluated the use of care bundles and extracorporeal techniques as potential therapeutic approaches. Here we provide graded recommendations for managing SA-AKI and highlight priorities for future research.

The rate and assessment of muscle wasting during critical illness: a systematic review and meta-analysis.

BACKGROUND: Patients with critical illness can lose more than 15% of muscle mass in one week, and this can have long-term detrimental effects. However, there is currently no synthesis of the data of intensive care unit (ICU) muscle wasting studies, so the true mean rate of muscle loss across all studies is unknown. The aim of this project was therefore to systematically synthetise data on the rate of muscle loss and to identify the methods used to measure muscle size and to synthetise data on the prevalence of ICU-acquired weakness in critically ill patients. METHODS: We conducted a systematic literature search of MEDLINE, PubMed, AMED, BNI, CINAHL, and EMCARE until January 2022 (International Prospective Register of Systematic Reviews [PROSPERO] registration: CRD420222989540. We included studies with at least 20 adult critically ill patients where the investigators measured a muscle mass-related variable at two time points during the ICU stay. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and assessed the study quality using the Newcastle-Ottawa Scale. RESULTS: Fifty-two studies that included 3251 patients fulfilled the selection criteria. These studies investigated the rate of muscle wasting in 1773 (55%) patients and assessed ICU-acquired muscle weakness in 1478 (45%) patients. The methods used to assess muscle mass were ultrasound in 85% (n = 28/33) of the studies and computed tomography in the rest 15% (n = 5/33). During the first week of critical illness, patients lost every day -1.75% (95% CI -2.05, -1.45) of their rectus femoris thickness or -2.10% (95% CI -3.17, -1.02) of rectus femoris cross-sectional area. The overall prevalence of ICU-acquired weakness was 48% (95% CI 39%, 56%). CONCLUSION: On average, critically ill patients lose nearly 2% of skeletal muscle per day during the first week of ICU admission.