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PurposeTo validate the furosemide stress test (FST) for predicting the progression of acute kidney injury (AKI).Materials and methodsWe performed a multicenter, prospective, observational study in patients with stage I or II AKI. The FST (1 mg/kg for loop diuretic naïve patients and 1.5 mg/kg in patients previously exposed to loop diuretics) was administered. Subsequent urinary flow rate (UFR) recorded and predictive ability of urinary output was measured by the area under the curve receiver operatic characteristics (AuROC). Primary outcome was progression to Stage III AKI. Secondary outcomes included in-hospital mortality and adverse events.ResultsWe studied 92 critically ill patients. 23 patients progressed to stage III AKI and had significantly lower UFR (p

Objective: Thombomodulin (TM) is an activator of protein C and a biomarker for endothelial injury. We hypothesized that (1) elevated plasma levels would be associated with clinical outcomes and (2) polymorphisms in the TM gene would be associated with plasma levels.

Background: No effective pharmacotherapy for acute respiratory distress syndrome (ARDS) exists, and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. We aimed to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS. Methods: The STem cells for ARDS Treatment (START) trial was a multicentre, open-label, dose-escalation, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by the acute onset of the need for positive pressure ventilation by an endotracheal or tracheal tube, a PaO2:FiO2 less than 200 mm Hg with at least 8 cm H2O positive end-expiratory airway pressure (PEEP), and bilateral infiltrates consistent with pulmonary oedema on frontal chest radiograph. The first three patients were treated with low dose MSCs (1 million cells/kg predicted bodyweight [PBW]), the next three patients received intermediate dose MSCs (5 million cells/kg PBW), and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT01775774. Findings: No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. Serious adverse events were subsequently noted in three patients during the weeks after the infusion: one patient died on study day 9, one patient died on study day 31, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate, but thought to have occurred before the MSC infusion based on MRI results. None of these severe adverse events were thought to be MSC-related. Interpretation: A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in nine patients with moderate to severe ARDS. Based on this phase 1 experience, we have proceeded to phase 2 testing of MSCs for moderate to severe ARDS with a primary focus on safety and secondary outcomes including respiratory, systemic, and biological endpoints. Funding: The National Heart, Lung, and Blood Institute.

Background: Organ dysfunction consequent to infection ('severe sepsis') is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to

Background Human bone marrow-derived mesenchymal stem (stromal) cells (hMSCs) improve survival in mouse models of acute respiratory distress syndrome (ARDS) and reduce pulmonary oedema in a perfused human lung preparation injured with Escherichia coli bacteria. We hypothesised that clinical grade hMSCs would reduce the severity of acute lung injury (ALI) and would be safe in a sheep model of ARDS. Methods Adult sheep (30-40 kg) were surgically prepared. After 5 days of recovery, ALI was induced with cotton smoke insufflation, followed by instillation of live Pseudomonas aeruginosa (2.51011 CFU) into both lungs under isoflurane anaesthesia. Following the injury, sheep were ventilated, resuscitated with lactated Ringer's solution and studied for 24 h. The sheep were randomly allocated to receive one of the following treatments intravenously over 1 h in one of the following groups: (1) control, PlasmaLyte A, n=8; (2) lower dose hMSCs, 5106 hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10106 hMSCs/kg, n=4. Results By 24 h, the PaO2/FiO2 ratio was significantly improved in both hMSC treatment groups compared with the control group (control group: PaO2/FiO2 of 9715 mm Hg; lower dose: 28855 mm Hg (p=0.003); higher dose: 3272 mm Hg ( p=0.003)). The median lung water content was lower in the higher-dose hMSCtreated group compared with the control group (higher dose: 5.0 g wet/g dry [IQR 4.9-5.8] vs control: 6.7 g wet/g dry [IQR 6.4-7.5] ( p=0.01)). The hMSCs had no adverse effects. Conclusions Human MSCs were well tolerated and improved oxygenation and decreased pulmonary oedema in a sheep model of severe ARDS.9999.

OBJECTIVES:: Cigarette smoke exposure has recently been found to be associated with increased susceptibility to trauma-and transfusion-associated acute respiratory distress syndrome. We sought to determine 1) the incidence of cigarette smoke exposure in a diverse multicenter sample of acute respiratory distress syndrome patients and 2) whether cigarette smoke exposure is associated with severity of lung injury and mortality in acute respiratory distress syndrome. DESIGN:: Analysis of the Albuterol for the Treatment of Acute Lung Injury and Omega Acute Respiratory Distress Syndrome Network studies. SETTING:: Acute Respiratory Distress Syndrome Network hospitals. PATIENTS:: Three hundred eighty-one patients with acute respiratory distress syndrome. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: 4-(Methylnitrosamino)-1-(3-pyridyl)-1- butanol, a validated tobacco-specific marker, was measured in urine samples from subjects enrolled in two National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network randomized controlled trials. Urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels were consistent with active smoking in 36% of acute respiratory distress syndrome patients and with passive smoking in 41% of nonsmokers (vs 20% and 40% in general population, respectively). Patients with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels in the active smoking range were younger and had a higher incidence of alcohol misuse, fewer comorbidities, lower severity of illness, and less septic shock at enrollment compared with patients with undetectable 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels. Despite this lower severity of illness, the severity of lung injury did not significantly differ based on biomarker-determined smoking status. Cigarette smoke exposure was not significantly associated with death after adjusting for differences in age, alcohol use, comorbidities, and severity of illness. CONCLUSIONS:: In this first multicenter study of biomarker-determined cigarette smoke exposure in acute respiratory distress syndrome patients, we found that active cigarette smoke exposure was significantly more prevalent among acute respiratory distress syndrome patients compared to population averages. Despite their younger age, better overall health, and lower severity of illness, smokers by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol had similar severity of lung injury as patients with undetectable 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol. These findings suggest that active cigarette smoking may increase susceptibility to acute respiratory distress syndrome in younger, healthier patients. © 2014 by the Society of Critical Care Medicine and Lippincott Williams and Wilkins.

Novel biomarkers may improve our ability to predict which patients with chronic kidney disease (CKD) are at higher risk for progressive loss of renal function. Here, we assessed the performance of urine neutrophil gelatinase-associated lipocalin (NGAL) for

End-stage renal disease (ESRD) and chronic kidney disease (CKD) are increasing health problems worldwide. In the US alone, an estimated 26 million people suffer from some form of CKD. In countries such as India and Pakistan, the prevalence of CKD is also rapidly rising. The presence of CKD is associated with increased perioperative morbidity and mortality, even when adjusted for other variables such as hypertension or diabetes. Frequently, CKD is under diagnosed, so patients and physicians are often unaware of the impaired renal function. Renal dysfunction as a predictor of perioperative outcomes is discussed together with therapeutic interventions aimed at the protection of renal function. Better interventions and diagnostic tools, such as cystatin C, are needed to further improve perioperative morbidity and mortality in patients with CKD.

Rationale: β₂-Adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies.Objectives: This clinical trial was designed to test the hypothesis that an aerosolized β₂-agonist, albuterol, would improve clinical outcomes in patients with acute lung injury (ALI).Methods: We conducted a multicenter, randomized, placebo-controlled clinical trial in which 282 patients with ALI receiving mechanical ventilation were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. The primary outcome variable for the trial was ventilator-free days.Measurements and Main Results: Ventilator-free days were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 d, respectively; 95% confidence interval for the difference, -4.7 to 0.3 d; P = 0.087). Rates of death before hospital discharge were not significantly different between the albuterol and placebo groups (23.0 and 17.7%, respectively; 95%confidence interval for the difference,-4.0 to 14.7%;P = 0.30). In the subset of patients with shock before randomization, the number of ventilator-free days was lower with albuterol, although mortality was not different. Overall, heart rates were significantly higher in the albuterol group by approximately 4 beats/minute in the first 2 days after randomization, but rates of new atrial fibrillation (10% in both groups) and other cardiac dysrhythmias were not significantly different.Conclusions: These results suggest that aerosolized albuterol does not improve clinical outcomes in patients with ALI. Routine use of β₂-agonist therapy in mechanically ventilated patients with ALI cannot be recommended. Clinical trial registered with www.clinicaltrials.gov (NCT 00434993). [ABSTRACT FROM AUTHOR]

Rationale: Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days.Objectives: To test the efficacy of activated protein C (APC) as a therapy for patients with ALI.Methods: Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days.Measurements and Main Results: APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups.Conclusions: APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity. [ABSTRACT FROM AUTHOR]

Objective: To identify biological and clinical predictors of acute kidney injury in subjects with acute lung injury.Design: Secondary data analysis from a multicenter, randomized clinical trial.Setting: Intensive care units in ten university medical centers.Patients: A total of 876 patients enrolled in the first National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial.Interventions: Study subjects were randomized to receive a low tidal volume ventilation strategy and pharmacologic therapy with ketoconazole or lisofylline in a factorial design.Measurements and Main Results: We tested the association of baseline levels of interleukin-6, interleukin-8, interleukin-10, von Willebrand factor, tumor necrosis factor-[alpha], type I and II soluble tumor necrosis factor receptors (sTNFR-I and -II), protein C, plasminogen activator inhibitor-1 (PAI-1), surfactant protein-A, surfactant protein-D, and intracellular adhesion molecule-1 with subsequent acute kidney injury. Of 876 study participants who did not have end-stage renal disease, 209 (24%) developed acute kidney injury, defined as a rise in serum creatinine of >50% from baseline over the first four study days. The 180-day mortality rate for subjects with acute kidney injury was 58%, compared with 28% in those without acute kidney injury (p < .001). Interleukin-6, sTNFR-I, sTNFR-II, and PAI-1 levels were independently associated with acute kidney injury after adjustment for demographics, interventions, and severity of illness. A combination of clinical and biological predictors had the best area under the receiver operating characteristic curve, and the contribution of sTNFR-I and PAI-1 to this model was highly significant (p = .0003).Conclusions: Elevations in PAI-1, interleukin-6, and the sTNFRs in subjects with acute kidney injury suggest that disordered coagulation, inflammation, and neutrophil-endothelial interactions play important roles in the pathogenesis of acute kidney injury. The combination of these biological and clinical risk factors may have important and additive value in predictive models for acute kidney injury. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: The primary objective of this study was to test whether an elevated systolic pulmonary artery (PA) pressure or an elevated pulmonary dead space fraction (Vd/Vt) in early acute lung injury (ALI) is associated with poor clinical outcomes in the era of lung-protective ventilation. DESIGN: Prospective observational cohort study. SETTING: ICUs of a university hospital. PATIENTS: Forty-two patients with ALI receiving mechanical ventilation. MEASUREMENTS: PA pressure was measured noninvasively using transthoracic echocardiography. Vd/Vt was measured by volumetric capnography (NICO Cardiopulmonary Management System; Novametrix; Wallingford, CT). MAIN RESULTS: There was no difference in the mean systolic PA pressure in patients who died compared to those who survived (43 +/- 9 mm Hg vs 41 +/- 9 mm Hg, p = 0.54) [mean +/- SD]. In contrast to the PA systolic pressure, Vd/Vt was significantly higher in patients who died compared to those who survived (0.61 +/- 0.09 vs 0.53 +/- 0.10, p = 0.02). Similarly, Vd/Vt was higher in patients with < 7 ventilator-free days during the first 28 days after enrollment compared to those with > 7 ventilator-free days (0.61 +/- 0.08 vs 0.52 +/- 0.11, p = 0.008). CONCLUSION: In the era of lung-protective ventilation, systolic PA pressure early in the course of ALI is elevated but not predictive of outcome. However, elevated Vd/Vt in early ALI is associated with increased mortality and with fewer ventilator-free days. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Despite technological advances in renal replacement therapy over the past few years, acute renal failure in the intensive care unit remains associated with high morbidity and mortality rates. In this article I review recent research aimed at elucidating mechanisms of renal recovery from acute injury. DESIGN: Review of the literature. CONCLUSIONS: A number of peptide growth hormones are reviewed, including epidermal growth factor, insulin-like growth factor-1, thyroxine, hepatocyte growth factor, and bone morphogenetic protein-7 promote renal regeneration in model systems. Unfortunately, despite promising studies in animal models of toxin and ischemia-induced acute tubular necrosis, human studies have not shown any clinical benefit. However, several of these molecules have not been studied in clinical trials. Existing pharmacologic strategies have a limited role in renal recovery. Finally, several recent studies have focused on the effects of renal replacement therapy on renal recovery, but additional studies are needed to confirm and extend these results. [ABSTRACT FROM AUTHOR]

Sewages from duck farms are often recognized as a major source of antimicrobial resistance and pathogenic bacteria discharged to natural water bodies, but few studies depicted the dynamic changes in resistome and microbial communities in the rivers under immense exposure of sewage discharge. In this study, we investigated the ecological and environmental risks of duck sewages to the rivers that geographically near to the duck farms with short-distance (<1 km) using 16S rRNA amplicon and metagenomic sequencing. The results showed that a total of 20 ARG types were identified with abundances ranged from 0.61 to 1.33 cpc. Of note, the genes modulate resistances against aminoglycoside, bacitracin and beta-lactam were the most abundant ARGs. Limnohabitans, Fluviibacter and Cyanobium were the top 3 predominant genera in the microbial community. The alpha diversity of overall microbial community decrease while the abundance of pathogen increase during the input of sewage within 200 m. Sul1 and bacA were the dominant ARGs brought from duck farm sewage. The community variations of ARGs and microbiome were primarily driven by pH and temperature. Total phosphorus was significantly correlated to alpha diversity and top 30 ARGs subtype. Stochastic processes was the dominated microbial assembly pattern and did not be altered by sewage. We also highlighted the ecological risk caused by bla GES which possibly could be mitigated by Cyanobacteria, and the natural water body can purify partial ARGs as well as microbiome from duck farms sewage. These findings expanded our knowledge regarding the ecological risks by wastes from the livestock farm, and underscoring the necessity to monitor ARGs in farm-surrounding water bodies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Hyponatremia is the most common electrolyte abnormality in hospitalized patients. Treatment of hyponatremia is associated with improved outcomes, but more than one in three cases of new onset hyponatremia is not corrected by the time of hospital discharge. Nephrologist input may improve the diagnosis and treatment of hyponatremia, but specialist resources are limited. Targeted automatic electronic consultations (TACos) may be one approach to provide expert nephrologist guidance to the workup and management of hyponatremia using a scalable model., Objective: Evaluate the feasibility and acceptability of a TACo intervention for hospitalized patients with hyponatremia., Design: Single-site, parallel-group cluster randomized trial., Participants: Adult inpatients with hyponatremia on the hospital medicine service., Interventions: A nephrologist conducted TACos on intervention patients, making diagnostic and therapeutic recommendations daily (if warranted) until discharge or resolution of hyponatremia., Main Measures: Measures of feasibility included the number of eligible participants, percentage receiving TACos, number of TACos per participant, and percentage of formal nephrology consults. Acceptability was assessed by a post-intervention survey. Clinical outcomes, including the percentage of hyponatremia cases that resolved by discharge, were also assessed., Key Results: We identified 62 patients who met inclusion criteria: 38 in the intervention group and 24 in the control group. A nephrologist determined that 26 of 38 intervention patients (68%) would likely benefit from diagnostic and management recommendations; 67 TACos were performed (mean 2.6 per patient). Fourteen of 18 primary team physicians (78%) reported that the e-consults changed their management, and 15 of 18 (83%) wanted TACOs to continue. Resolution of hyponatremia, length of stay, 30-day readmissions, and costs were similar in the intervention and control groups., Conclusions: Inpatient TACos for hyponatremia were feasible and acceptable to primary teams, and frequently led to changes in diagnosis and management. Further studies are needed to determine the impact of the TACo model on clinical outcomes and cost-effectiveness., (© 2024. The Author(s).)

Background: Only a subset of patients at risk for ARDS go on to develop it, and the contribution of preexisting comorbidities (eg, diabetes) to ARDS risk is not well understood. Prior studies of the association between diabetes and ARDS have yielded conflicting results., Research Question: Does assessing ARDS risk based on hemoglobin A1c (HbA1c) as a marker of long-term blood glucose levels, rather than a charted diagnosis of diabetes, clarify the relationship between diabetes and ARDS?, Study Design and Methods: Using data from two prospective observational cohorts of critically ill adults (Validating Acute Lung Injury Biomarkers for Diagnosis [VALID] and Early Assessment of Renal and Lung Injury [EARLI]), we analyzed the association between clinical HbA1c category and development of ARDS in patients with a risk factor for ARDS and at least one clinical HbA1c measurement within the 180 days prior through 14 days after enrollment., Results: A total of 599 patients in VALID and 276 in EARLI met inclusion criteria, of whom 164 and 58 developed ARDS, respectively. Patients with a charted diagnosis of diabetes were not shown to be more likely to develop ARDS (VALID: 24.6% ARDS in those categorized as nondiabetic vs 30.0% in those categorized as diabetic, P = .14; EARLI: 19.6% vs 22.8%, respectively; P = .55). However, in VALID, patients categorized as diabetic with inadequate glycemic control based on their HbA1c had an increased risk of developing ARDS compared with those with nondiabetic HbA1c (20.9% vs 34.0%, respectively; P = .0073), a finding that persisted in multivariable analysis (OR for those categorized as diabetic with inadequate glycemic control vs those categorized as nondiabetic range HbA1c, 1.25; 95% CI, 1.01-1.57). These findings were not reproduced in the smaller EARLI cohort, but were appreciated when the cohorts were combined for analysis., Interpretation: Elevated HbA1c may be associated with risk of developing ARDS, independent of clinical diagnosis of diabetes, but prospective validation is needed. If confirmed, these findings suggest that inadequate glycemic control could be an unrecognized risk factor for ARDS., Competing Interests: Financial/Nonfinancial Disclosures None declared.

Purpose: Novel interventions for the prevention or treatment of acute kidney injury (AKI) are currently lacking. To facilitate the evaluation and adoption of new treatments, the use of the most appropriate design and endpoints for clinical trials in AKI is critical and yet there is little consensus regarding these issues. We aimed to develop recommendations on endpoints and trial design for studies of AKI prevention and treatment interventions based on existing data and expert consensus., Methods: At the 31st Acute Disease Quality Initiative (ADQI) meeting, international experts in critical care, nephrology, involving adults and pediatrics, biostatistics and people with lived experience (PWLE) were assembled. We focused on four main areas: (1) patient enrichment strategies, (2) prevention and attenuation studies, (3) treatment studies, and (4) innovative trial designs of studies other than traditional (parallel arm or cluster) randomized controlled trials. Using a modified Delphi process, recommendations and consensus statements were developed based on existing data, with > 90% agreement among panel members required for final adoption., Results: The panel developed 12 consensus statements for clinical trial endpoints, application of enrichment strategies where appropriate, and inclusion of PWLE to inform trial designs. Innovative trial designs were also considered., Conclusion: The current lack of specific therapy for prevention or treatment of AKI demands refinement of future clinical trial design. Here we report the consensus findings of the 31st ADQI group meeting which has attempted to address these issues including the use of predictive and prognostic enrichment strategies to enable appropriate patient selection., (© 2024. The Author(s).)

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates., Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo., Design, Setting, and Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation., Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days., Main Outcome and Measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL., Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, -1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, -6.3; 95% CI, -10.8 to -1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen., Conclusions and Relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients., Trial Registration: ClinicalTrials.gov Identifier: NCT04291508.

Purpose: The development of acute kidney injury (AKI) after the acute respiratory distress syndrome (ARDS) reduces the chance of organ recovery and survival. The purpose of this study was to examine the AKI rate and attributable mortality in ARDS patients., Methods: We performed an individual patient-data analysis including 10 multicenter randomized controlled trials conducted over 20 years. We employed a Super Learner ensemble technique, including a time-dependent analysis, to estimate the adjusted risk of AKI. We calculated the mortality attributable to AKI using an inverse probability of treatment weighting estimator integrated with the Super Learner., Results: There were 5148 patients included in this study. The overall incidence of AKI was 43.7% (n = 2251). The adjusted risk of AKI ranged from 38.8% (95% confidence interval [CI], 35.7 to 41.9%) in ARMA, to 55.8% in ROSE (95% CI, 51.9 to 59.6%). 37.1% recovered rapidly from AKI, with a significantly lower recovery rate in recent trials (P < 0.001). The 90-day excess in mortality attributable to AKI was 15.4% (95% CI, 12.8 to 17.9%). It decreased from 25.4% in ARMA (95% CI, 18.7 to 32%), to 11.8% in FACTT (95% CI, 5.5 to 18%) and then remained rather stable over time. The 90-day overall excess in mortality attributable to acute kidney disease was 28.4% (95% CI, 25.3 to 31.5%)., Conclusions: The incidence of AKI appears to be stable over time in patients with ARDS enrolled in randomized trials. The development of AKI remains a significant contributing factor to mortality. These estimates are essential for designing future clinical trials for AKI prevention or treatment., (© 2024. The Author(s).)

Background and Objectives: Treatment selection for brain arteriovenous malformations (BAVMs) is complicated by BAVM size, location, and hemodynamics. Quantitative digital subtraction angiography is used to quantify the hemodynamic impact of BAVMs on cerebral circulation. This study investigated the association between cerebral circulation time and the complete obliteration (CO) rate of BAVMs after stereotactic radiosurgery (SRS)., Methods: We analyzed the data of 143 patients who underwent SRS for BAVMs between January 2011 and December 2019 in our institute. Their pre-SRS magnetic resonance imaging and angiography images were analyzed to acquire BAVM characteristics and quantitative digital subtraction angiography parameters. Modified cerebral circulation time (mCCT) was defined as the time difference between the bolus arrival time of the ipsilateral cavernous internal carotid artery and that of the parietal vein, as determined from the lateral view of images obtained using digital subtraction angiography. Cox regression with hazard ratios and Kaplan-Meier analyses were conducted to determine the associations between the parameters and BAVM CO after SRS., Results: Of the 143 patients, 101 (70.6%) achieved BAVM CO. According to the multivariate analyses, an increased mCCT (hazard ratio: 1.24, P = .041) was the independent factor associated with BAVM CO after adjustment for age, sex, hemorrhagic presentation, a BAVM volume of >5 cm3, and a margin dose of >18 Gy. Individuals with an mCCT of ≤2.32 s had a lower 36-month probability of BAVM CO than did those with an mCCT of >2.32 s (44.1% ± 6.8% vs 63.3% ± 5.6%, P = .034)., Conclusion: The hemodynamic impact of high-flow BAVM demonstrated by a shortened mCCT is associated with a lower BAVM CO rate after SRS., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Background: Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAF ARDS ) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype., Methods: We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAF ARDS in patients with sepsis was estimated separately in the hypo and hyperinflammatory phenotypes. Organ dysfunction, severe comorbidities, and withdrawal of life support were abstracted from the medical record in a subset of patients from the EARLI cohort who died (n = 130/179). Primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support., Results: The PAF ARDS was 19% (95%CI 10,28%) in hypoinflammatory sepsis and, 14% (95%CI 6,20%) in hyperinflammatory sepsis. Cause of death differed between the two phenotypes (p < 0.001). Respiratory failure was the most common cause of death in hypoinflammatory sepsis, whereas circulatory shock was the most common cause in hyperinflammatory sepsis. Death with severe underlying comorbidities was more frequent in hypoinflammatory sepsis (81% vs. 67%, p = 0.004)., Conclusions: The PAF ARDS is modest in both phenotypes whereas primary cause of death among patients with sepsis differed substantially by phenotype. This study identifies challenges in powering future clinical trials to detect changes in mortality outcomes among patients with sepsis and ARDS., (© 2024. The Author(s).)

Background: Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes., Methods: We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted at two sites, one tertiary care center and one urban safety net hospital. RIARDS was defined according to previous studies as improvement of hypoxemia defined as (i) PaO 2 :FiO 2  > 300 or (ii) SpO2: FiO 2  > 315 on the day following diagnosis of ARDS (day 2) or (iii) unassisted breathing by day 2 and for the next 48 h (defined as absence of endotracheal intubation on day 2 through day 4). Plasma biomarkers were measured on samples collected on the day of study enrollment, and ARDS phenotypes were allocated as previously described., Results: RIARDS accounted for 21% of all ARDS participants. Patients with RIARDS had better clinical outcomes compared to those with persistent ARDS, with lower hospital mortality (13% vs. 57%; p value < 0.001) and more ICU-free days (median 24 vs. 0; p value < 0.001). Plasma levels of interleukin-6, interleukin-8, and plasminogen activator inhibitor-1 were significantly lower among patients with RIARDS. The hypoinflammatory phenotype of ARDS was more common among patients with RIARDS (78% vs. 51% in persistent ARDS; p value = 0.001)., Conclusions: This study identifies a high prevalence of RIARDS in a multicenter observational cohort and confirms the more benign clinical course of these patients. We report the novel finding that RIARDS is characterized by lower concentrations of plasma biomarkers of inflammation compared to persistent ARDS, and that hypoinflammatory ARDS is more prevalent among patients with RIARDS. Identification and exclusion of RIARDS could potentially improve prognostic and predictive enrichment in clinical trials., (© 2024. The Author(s).)

Objective: Recent clinical guidelines for sepsis management emphasize immediate antibiotic initiation for suspected septic shock. Though hypotension is a high-risk marker of sepsis severity, prior studies have not considered the precise timing of hypotension in relation to antibiotic initiation and how clinical characteristics and outcomes may differ. Our objective was to evaluate antibiotic initiation in relation to hypotension to characterize differences in sepsis presentation and outcomes in patients with suspected septic shock., Methods: Adults presenting to the emergency department (ED) June 2012-December 2018 diagnosed with sepsis (Sepsis-III electronic health record [EHR] criteria) and hypotension (non-resolving for ≥30 min, systolic blood pressure <90 mmHg) within 24 h. We categorized patients who received antibiotics before hypotension ("early"), 0-60 min after ("immediate"), and >60 min after ("late") treatment., Results: Among 2219 patients, 55% received early treatment, 13% immediate, and 32% late. The late subgroup often presented to the ED with hypotension (median 0 min) but received antibiotics a median of 191 min post-ED presentation. Clinical characteristics notable for this subgroup included higher prevalence of heart failure and liver disease ( p  < 0.05) and later onset of systemic inflammatory response syndrome (SIRS) criteria compared to early/immediate treatment subgroups (median 87 vs. 35 vs. 20 min, p  < 0.0001). After adjustment, there was no difference in clinical outcomes among treatment subgroups., Conclusions: There was significant heterogeneity in presentation and timing of antibiotic initiation for suspected septic shock. Patients with later treatment commonly had hypotension on presentation, had more hypotension-associated comorbidities, and developed overt markers of infection (eg, SIRS) later. While these factors likely contribute to delays in clinician recognition of suspected septic shock, it may not impact sepsis outcomes., Competing Interests: Dr Prasad and Ms. Oreper report personal fees from EpiExcellence, LLC, outside the submitted work. The other authors have no conflicts of interest., (© 2024 The Authors. Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Rationale: Two molecular phenotypes have been identified in acute respiratory distress syndrome (ARDS). In the ROSE (Reevaluation of Systemic Early Neuromuscular Blockade) trial of cisatracurium in moderate to severe ARDS, we addressed three unanswered questions: 1 ) Do the same phenotypes emerge in a more severe ARDS cohort with earlier recruitment; 2 ) Do phenotypes respond differently to neuromuscular blockade? and 3 ) What biological pathways most differentiate inflammatory phenotypes? Methods: We performed latent class analysis in ROSE using preenrollment clinical and protein biomarkers. In a subset of patients ( n  = 134), we sequenced whole-blood RNA using enrollment and Day 2 samples and performed differential gene expression and pathway analyses. Informed by the differential gene expression analysis, we measured additional plasma proteins and evaluated their abundance relative to gene expression amounts. Measurements and Main Results: In ROSE, we identified the hypoinflammatory (60.4%) and hyperinflammatory (39.6%) phenotypes with similar biological and clinical characteristics as prior studies, including higher mortality at Day 90 for the hyperinflammatory phenotype (30.3% vs. 61.6%; P  < 0.0001). We observed no treatment interaction between the phenotypes and randomized groups for mortality. The hyperinflammatory phenotype was enriched for genes associated with innate immune response, tissue remodeling, and zinc metabolism at Day 0 and collagen synthesis and neutrophil degranulation at Day 2. Longitudinal changes in gene expression patterns differed dependent on survivorship. For most highly expressed genes, we observed correlations with their corresponding plasma proteins' abundance. However, for the class-defining plasma proteins in the latent class analysis, no correlation was observed with their corresponding genes' expression. Conclusions: The hyperinflammatory and hypoinflammatory phenotypes have different clinical, protein, and dynamic transcriptional characteristics. These findings support the clinical and biological potential of molecular phenotypes to advance precision care in ARDS.