Risk factors and outcome associated with fungal infections in patients with severe burn injury: 10-year retrospective IFI-BURN study.

BACKGROUND: In burn patients, skin barrier disruption and immune dysfunctions increase susceptibility to invasive fungal diseases (IFDs) like invasive candidiasis (IC) and invasive mold infections (IMI). We provide an in-depth analysis of IFD-related factors and outcomes in a 10-year cohort of severe burn patients. METHOD: Retrospective cohort study including adult patients admitted to the Burn Intensive Care Unit (BICU) between April 2014 and May 2023 with Total Burn Surface Area (TBSA) ≥15%. Patients were classified as proven IFD according to EORTC/MSGERC criteria applicable for IC. Putative IMIs were defined with: ≥2 positive cultures from a skin biopsy/bronchoalveolar lavage OR ≥2 positive blood specific-qPCRs OR a combination of both. RESULTS: Among 1381 patients admitted, 276 consecutive patients with TBSA ≥15% were included. Eighty-seven (31.5%; IC n=30; IMI n=43; both n=14) patients fulfilled the criteria for probable/putative IFD. At Day 30 after the burn injury, the estimated cumulative incidence pr/pu IFD was 26.4% (95%CI 21.4-31.8%). Factors independently associated with IFDs were TBSA, severity scores and indoor burn injury (i.e., from confined space fire). Overall mortality was 15.3% and 36.8% in the no IFD, pr/pu IFD groups respectively (p<0.0001). IFD was independently associated with a risk of death (HR: 1.94 for pr/pu IFD; 95%CI, 1.12-3.36; p=0.019). DISCUSSION: This study describes 21st-century characteristics of IFDs in sever burn patients confirming known risk factors with thresholds and identifying the indoor injury as an independent factor associated to IFDs. This suggests a link to contamination caused by fire damage, which is highly susceptible to aerosolizing spores.

Position Paper on the Reporting of Norepinephrine Formulations in Critical Care from the Society of Critical Care Medicine and European Society of Intensive Care Medicine Joint Task Force.

OBJECTIVES: To provide guidance on the reporting of norepinephrine formulation labeling, reporting in publications, and use in clinical practice. DESIGN: Review and task force position statements with necessary guidance. SETTING: A series of group conference calls were conducted from August 2023 to October 2023, along with a review of the available evidence and scope of the problem. SUBJECTS: A task force of multinational and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. INTERVENTIONS: The implications of a variation in norepinephrine labeled as conjugated salt (i.e., bitartrate or tartrate) or base drug in terms of effective concentration of norepinephrine were examined, and guidance was provided. MEASUREMENTS AND MAIN RESULTS: There were significant implications for clinical care, dose calculations for enrollment in clinical trials, and results of datasets reporting maximal norepinephrine equivalents. These differences were especially important in the setting of collaborative efforts across countries with reported differences. CONCLUSIONS: A joint task force position statement was created outlining the scope of norepinephrine-dose formulation variations, and implications for research, patient safety, and clinical care. The task force advocated for a uniform norepinephrine-base formulation for global use, and offered advice aimed at appropriate stakeholders.

Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials.

Acute kidney injury (AKI) often complicates sepsis and is associated with high morbidity and mortality. In recent years, several important clinical trials have improved our understanding of sepsis-associated AKI (SA-AKI) and impacted clinical care. Advances in sub-phenotyping of sepsis and AKI and clinical trial design offer unprecedented opportunities to fill gaps in knowledge and generate better evidence for improving the outcome of critically ill patients with SA-AKI. In this manuscript, we review the recent literature of clinical trials in sepsis with focus on studies that explore SA-AKI as a primary or secondary outcome. We discuss lessons learned and potential opportunities to improve the design of clinical trials and generate actionable evidence in future research. We specifically discuss the role of enrichment strategies to target populations that are most likely to derive benefit and the importance of patient-centered clinical trial endpoints and appropriate trial designs with the aim to provide guidance in designing future trials.

Should renin-angiotensin system inhibitors be held prior to major surgery?

Many patients undergoing surgical procedures have a history of hypertension, diabetes mellitus, heart failure, or a combination. Often, these conditions involve the chronic use of a renin-angiotensin system inhibitor, including angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). Observational studies have suggested that continuing ACEIs/ARBs before major noncardiac surgery can increase the risk of intraoperative hypotension, which might drive postoperative complications such as acute kidney injury, myocardial injury, or stroke. Strong recommendations on how to manage ACEIs/ARBs before surgery are, however, lacking owing to insufficient evidence, mostly limited to data from observational studies. Recently, the SPACE trial investigated the impact of preoperative management of ACEIs/ARBs on postoperative myocardial injury. Myocardial injury occurred in 48.3% patients randomised to discontinue and 41.3% patients randomised to continue ACEI/ARB (odds ratio for continuing: 0.77, 95% confidence interval 0.45-1.31). Patients randomised to the 'Stop' group experienced more postoperative hypertension. In a post hoc analysis, patients randomised to the 'Continue' group with low preoperative NT-proBNP concentrations (<100 pg ml-1) experienced less myocardial injury after surgery than the 'Stop' group, whereas no significant difference was observed in patients with elevated preoperative NT-proBNP concentrations. The SPACE trial provides important and new reassuring data on the safety of continuing ACEIs/ARBs before major surgery, challenging previous beliefs.

Association between peripheral perfusion index and postoperative acute kidney injury in major noncardiac surgery patients receiving continuous vasopressors: a post hoc exploratory analysis of the VEGA-1 trial.

BACKGROUND: The peripheral perfusion index is the ratio of pulsatile to nonpulsatile static blood flow obtained by photoplethysmography and reflects peripheral tissue perfusion. We investigated the association between intraoperative perfusion index and postoperative acute kidney injury in patients undergoing major noncardiac surgery and receiving continuous vasopressor infusions. METHODS: In this exploratory post hoc analysis of a pragmatic, cluster-randomised, multicentre trial, we obtained areas and cumulative times under various thresholds of perfusion index and investigated their association with acute kidney injury in multivariable logistic regression analyses. In secondary analyses, we investigated the association of time-weighted average perfusion index with acute kidney injury. The 30-day mortality was a secondary outcome. RESULTS: Of 2534 cases included, 8.9% developed postoperative acute kidney injury. Areas and cumulative times under a perfusion index of 3% and 2% were associated with an increased risk of acute kidney injury; the strongest association was observed for area under a perfusion index of 1% (adjusted odds ratio [aOR] 1.32, 95% confidence interval [CI] 1.00-1.74, P=0.050, per 100%∗min increase). Additionally, time-weighted average perfusion index was associated with acute kidney injury (aOR 0.82, 95% CI 0.74-0.91, P<0.001) and 30-day mortality (aOR 0.68, 95% CI 0.49-0.95, P=0.024). CONCLUSIONS: Larger areas and longer cumulative times under thresholds of perfusion index and lower time-weighted average perfusion index were associated with postoperative acute kidney injury in patients undergoing major noncardiac surgery and receiving continuous vasopressor infusions. CLINICAL TRIAL REGISTRATION: NCT04789330.

Postoperative thrombotic events following major surgery in patients with a history of COVID-19: a retrospective cohort analysis of commercially insured beneficiaries in the USA.

PURPOSE: We sought to evaluate the synergistic risk of postoperative thrombosis in patients with a history of COVID-19 who undergo major surgery. Major surgery and SARS-CoV-2 infection are independently associated with an increased risk of thrombosis, but the magnitude of additional risk beyond surgery conferred by a COVID-19 history on the development of perioperative thrombotic events has not been clearly elucidated in the literature. METHODS: We conducted a retrospective cohort study among commercially insured adults in the USA from March 2020 to June 2021 using the Optum Labs Data Warehouse (OLDW), a longitudinal, real-world data asset containing deidentified administrative claims and electronic health records. We compared patients with prior COVID-19 who underwent surgery with control individuals who underwent surgery without a COVID-19 history and with control individuals who did not undergo surgery with and without a COVID-19 history. We assessed the interaction of surgery and previous COVID-19 on perioperative thrombotic events (venous thromboembolism and major adverse cardiovascular events) within 90 days using multivariable logistic regression and interaction analysis. RESULTS: Two million and two-hundred thousand eligible patients were identified from the OLDW. Patients in the surgical cohorts were older and more medically complex than nonsurgical population controls. After adjusting for confounders, only surgical exposure-not COVID-19 history-remained associated with perioperative thrombotic events (adjusted odds ratio [aOR], 4.07; 95% confidence interval [CI], 3.81 to 4.36). The multiplicative interaction term (aOR, 1.25; 95% CI, 0.96 to 1.61) and the synergy index (0.76; 95% CI, 0.56 to 1.04) suggest minimal effect modification of prior COVID-19 on surgery with regards to overall thrombotic risk. CONCLUSIONS: We found no evidence of synergistic thrombotic risk from previous COVID-19 in patients who underwent selected major surgery relative to the baseline thrombotic risk from surgery alone.

RéSUMé: OBJECTIF: Nous avons cherché à évaluer le risque synergique de thrombose postopératoire chez les patient·es ayant des antécédents de COVID-19 qui bénéficient d'une intervention chirurgicale majeure. La chirurgie majeure et l'infection par le SRAS-CoV-2 sont indépendamment associées à un risque accru de thrombose, mais l'ampleur du risque supplémentaire d'apparition de complications thrombotiques périopératoires, au-delà de la chirurgie et conféré par des antécédents de COVID-19, n'a pas été clairement élucidée dans la littérature. MéTHODE: Nous avons mené une étude de cohorte rétrospective auprès d'adultes assuré·es commercialement aux États-Unis de mars 2020 à juin 2021 à l'aide de la base de données Optum Labs Data Warehouse (OLDW), un actif de données longitudinales du monde réel contenant des requêtes administratives anonymisées et des dossiers de santé électroniques. Nous avons comparé les patient·es ayant déjà souffert de COVID-19 et ayant bénéficié d'une intervention chirurgicale avec des personnes témoins ayant bénéficié d'une intervention chirurgicale sans antécédents de COVID-19 et avec des personnes témoins n'ayant pas bénéficié de chirurgie, avec et sans antécédents de COVID-19. Nous avons évalué l'interaction de la chirurgie et des antécédents de COVID-19 avec les complications thrombotiques périopératoires (thromboembolie veineuse et événements cardiovasculaires indésirables majeurs) dans les 90 jours à l'aide d'une régression logistique multivariée et d'une analyse des interactions. RéSULTATS: Deux millions deux cent mille personnes admissibles ont été identifiées à partir du registre OLDW. Les patient·es des cohortes chirurgicales étaient plus âgé·es et présentaient une plus grande complexité médicale que les personnes témoins de la population non chirurgicale. Après ajustement pour tenir compte des facteurs de confusion, seule l'exposition chirurgicale ­ et non les antécédents de COVID-19 ­ est restée associée aux complications thrombotiques périopératoires (rapport de cotes ajusté [RCa], 4,07; intervalle de confiance [IC] à 95 %, 3,81 à 4,36). Le terme d'interaction multiplicative (RCa, 1,25; IC 95 %, 0,96 à 1,61) et l'indice de synergie (0,76; IC 95 %, 0,56 à 1,04) suggèrent une modification minimale de l'effet d'un diagnostic antérieur de COVID-19 sur la chirurgie en matière de risque thrombotique global. CONCLUSION: Nous n'avons trouvé aucune preuve de risque thrombotique synergique lié à une COVID-19 antérieure chez les patient·es ayant bénéficié d'une intervention chirurgicale par rapport au risque thrombotique de base lié à la chirurgie seule.

Low-Dose Corticosteroids for Critically Ill Adults With Severe Pulmonary Infections: A Review.

Importance: Severe pulmonary infections, including COVID-19, community-acquired pneumonia, influenza, and Pneumocystis pneumonia, are a leading cause of death among adults worldwide. Pulmonary infections in critically ill patients may cause septic shock, acute respiratory distress syndrome, or both, which are associated with mortality rates ranging between 30% and 50%. Observations: Corticosteroids mitigate the immune response to infection and improve outcomes for patients with several types of severe pulmonary infections. Low-dose corticosteroids, defined as less than or equal to 400 mg hydrocortisone equivalent daily, can reduce mortality of patients with severe COVID-19, community-acquired pneumonia, and Pneumocystis pneumonia. A randomized clinical trial of 6425 patients hospitalized with COVID-19 who required supplemental oxygen or noninvasive or invasive mechanical ventilation reported that dexamethasone 6 mg daily for 10 days decreased 28-day mortality (23% vs 26%). A meta-analysis that included 7 randomized clinical trials of 1689 patients treated in the intensive care unit for severe bacterial community-acquired pneumonia reported that hydrocortisone equivalent less than or equal to 400 mg daily for 8 days or fewer was associated with lower 30-day mortality compared with placebo (10% vs 16%). In a meta-analysis of 6 randomized clinical trials, low-dose corticosteroids were associated with lower mortality rates compared with placebo for patients with HIV and moderate to severe Pneumocystis pneumonia (13% vs 25%). In a predefined subgroup analysis of a trial of low-dose steroid treatment for septic shock, patients with community-acquired pneumonia randomized to 7 days of intravenous hydrocortisone 50 mg every 6 hours and fludrocortisone 50 µg daily had decreased mortality compared with the placebo group (39% vs 51%). For patients with acute respiratory distress syndrome caused by various conditions, low-dose corticosteroids were associated with decreased in-hospital mortality (34% vs 45%) according to a meta-analysis of 8 studies that included 1091 patients. Adverse effects of low-dose corticosteroids may include hyperglycemia, gastrointestinal bleeding, neuropsychiatric disorders, muscle weakness, hypernatremia, and secondary infections. Conclusions and Relevance: Treatment with low-dose corticosteroids is associated with decreased mortality for patients with severe COVID-19 infection, severe community-acquired bacterial pneumonia, and moderate to severe Pneumocystis pneumonia (for patients with HIV). Low-dose corticosteroids may also benefit critically ill patients with respiratory infections who have septic shock, acute respiratory distress syndrome, or both.

Intraoperative Use of Albumin in Major Noncardiac Surgery: Incidence, Variability, and Association With Outcomes.

BACKGROUND: The impact of albumin use during major surgery is unknown, and a dearth of evidence governing its use in major noncardiac surgery has long precluded its standardization in clinical guidelines. OBJECTIVE: In this study, we investigate institutional variation in albumin use among medical centers in the United States during major noncardiac surgery and explore the association of intraoperative albumin administration with important postoperative outcomes. METHODS: The study is an observational retrospective cohort analysis performed among 54 U.S. hospitals in the Multicenter Perioperative Outcomes Group and includes adult patients who underwent major noncardiac surgery under general anesthesia between January 2014 and June 2020. The primary endpoint was the incidence of albumin administration. Secondary endpoints are acute kidney injury (AKI), net-positive fluid balance, pulmonary complications, and 30-day mortality. Albumin-exposed and albumin-unexposed cases were compared within a propensity score-matched cohort to evaluate associations of albumin use with outcomes. RESULTS: Among 614,215 major surgeries, predominantly iso-oncotic albumin was administered in 15.3% of cases and featured significant inter-institutional variability in use patterns. Cases receiving intraoperative albumin involved patients of higher American Society of Anesthesiologists physical status and featured larger infused crystalloid volumes, greater blood loss, and vasopressor use. Overall, albumin was most often administered at high-volume surgery centers with academic affiliation, and within a propensity score-matched cohort (n=153,218), the use of albumin was associated with AKI (aOR 1.24, 95% CI 1.20-1.28, P <0.001), severe AKI (aOR 1.45, 95% CI 1.34-1.56, P <0.001), net-positive fluid balance (aOR 1.18, 95% CI 1.16-1.20, P <0.001), pulmonary complications (aOR 1.56, 95% CI 1.30-1.86, P <0.001), and 30-day all-cause mortality (aOR 1.37, 95% CI 1.26-1.49, P <0.001). CONCLUSIONS: Intravenous albumin is commonly administered among noncardiac surgeries with significant inter-institutional variability in use in the United States. Albumin administration was associated with an increased risk of postoperative complications.

Overcoming barriers in the design and implementation of clinical trials for acute kidney injury: a report from the 2020 Kidney Disease Clinical Trialists meeting.

Acute kidney injury (AKI) is a growing epidemic and is independently associated with increased risk of death, chronic kidney disease (CKD) and cardiovascular events. Randomized-controlled trials (RCTs) in this domain are notoriously challenging and many clinical studies in AKI have yielded inconclusive findings. Underlying this conundrum is the inherent heterogeneity of AKI in its etiology, presentation and course. AKI is best understood as a syndrome and identification of AKI subphenotypes is needed to elucidate the disease's myriad etiologies and to tailor effective prevention and treatment strategies. Conventional RCTs are logistically cumbersome and often feature highly selected patient populations that limit external generalizability and thus alternative trial designs should be considered when appropriate. In this narrative review of recent developments in AKI trials based on the Kidney Disease Clinical Trialists (KDCT) 2020 meeting, we discuss barriers to and strategies for improved design and implementation of clinical trials for AKI patients, including predictive and prognostic enrichment techniques, the use of pragmatic trials and adaptive trials.

The role of renin-angiotensin system in sepsis-associated acute kidney injury: mechanisms and therapeutic implications.

PURPOSE OF REVIEW: This review aims to explore the relationship between the renin angiotensin system (RAS) and sepsis-associated acute kidney injury (SA-AKI), a common complication in critically ill patients associated with mortality, morbidity, and long-term cardiovascular complications. Additionally, this review aims to identify potential therapeutic approaches to intervene with the RAS and prevent the development of AKI. RECENT FINDINGS: Recent studies have provided increasing evidence of RAS alteration during sepsis, with systemic and local RAS disturbance, which can contribute to SA-AKI. Angiotensin II was recently approved for catecholamine resistant vasodilatory shock and has been associated with improved outcomes in selected patients. SUMMARY: SA-AKI is a common condition that can involve disturbances in the RAS, particularly the canonical angiotensin-converting enzyme (ACE) angiotensin-II (Ang II)/angiotensin II receptor 1 (AT-1R) axis. Increased renin levels, a key enzyme in the RAS, have been shown to be associated with AKI and may also guide vasopressor therapy in shock. In patients with high renin levels, angiotensin II administration may reduce renin concentration, improve intra-renal hemodynamics, and enhance signaling through the angiotensin II receptor 1. Further studies are needed to explore the role of the RAS in SA-AKI and the potential for targeted therapies.

The alternative renin-angiotensin system in critically ill patients: pathophysiology and therapeutic implications.

The renin-angiotensin system (RAS) plays a crucial role in regulating blood pressure and the cardio-renal system. The classical RAS, mainly mediated by angiotensin I, angiotensin-converting enzyme, and angiotensin II, has been reported to be altered in critically ill patients, such as those in vasodilatory shock. However, recent research has highlighted the role of some components of the counterregulatory axis of the classical RAS, termed the alternative RAS, such as angiotensin-converting Enzyme 2 (ACE2) and angiotensin-(1-7), or peptidases which can modulate the RAS like dipeptidyl-peptidase 3, in many critical situations. In cases of shock, dipeptidyl-peptidase 3, an enzyme involved in the degradation of angiotensin and opioid peptides, has been associated with acute kidney injury and mortality and preclinical studies have tested its neutralization. Angiotensin-(1-7) has been shown to prevent septic shock development and improve outcomes in experimental models of sepsis. In the context of experimental acute lung injury, ACE2 activity has demonstrated a protective role, and its inactivation has been associated with worsened lung function, leading to the use of active recombinant human ACE2, in preclinical and human studies. Angiotensin-(1-7) has been tested in experimental models of acute lung injury and in a recent randomized controlled trial for patients with COVID-19 related hypoxemia. Overall, the alternative RAS appears to have a role in the pathogenesis of disease in critically ill patients, and modulation of the alternative RAS may improve outcomes. Here, we review the available evidence regarding the methods of analysis of the RAS, pathophysiological disturbances of this system, and discuss how therapeutic manipulation may improve outcomes in the critically ill.

An international RAND/UCLA expert panel to determine the optimal diagnosis and management of burn inhalation injury.

BACKGROUND: Burn inhalation injury (BII) is a major cause of burn-related mortality and morbidity. Despite published practice guidelines, no consensus exists for the best strategies regarding diagnosis and management of BII. A modified DELPHI study using the RAND/UCLA (University of California, Los Angeles) Appropriateness Method (RAM) systematically analysed the opinions of an expert panel. Expert opinion was combined with available evidence to determine what constitutes appropriate and inappropriate judgement in the diagnosis and management of BII. METHODS: A 15-person multidisciplinary panel comprised anaesthetists, intensivists and plastic surgeons involved in the clinical management of major burn patients adopted a modified Delphi approach using the RAM method. They rated the appropriateness of statements describing diagnostic and management options for BII on a Likert scale. A modified final survey comprising 140 statements was completed, subdivided into history and physical examination (20), investigations (39), airway management (5), systemic toxicity (23), invasive mechanical ventilation (29) and pharmacotherapy (24). Median appropriateness ratings and the disagreement index (DI) were calculated to classify statements as appropriate, uncertain, or inappropriate. RESULTS: Of 140 statements, 74 were rated as appropriate, 40 as uncertain and 26 as inappropriate. Initial intubation with ≥ 8.0 mm endotracheal tubes, lung protective ventilatory strategies, initial bronchoscopic lavage, serial bronchoscopic lavage for severe BII, nebulised heparin and salbutamol administration for moderate-severe BII and N-acetylcysteine for moderate BII were rated appropriate. Non-protective ventilatory strategies, high-frequency oscillatory ventilation, high-frequency percussive ventilation, prophylactic systemic antibiotics and corticosteroids were rated inappropriate. Experts disagreed (DI ≥ 1) on six statements, classified uncertain: the use of flexible fiberoptic bronchoscopy to guide fluid requirements (DI = 1.52), intubation with endotracheal tubes of internal diameter < 8.0 mm (DI = 1.19), use of airway pressure release ventilation modality (DI = 1.19) and nebulised 5000IU heparin, N-acetylcysteine and salbutamol for mild BII (DI = 1.52, 1.70, 1.36, respectively). CONCLUSIONS: Burns experts mostly agreed on appropriate and inappropriate diagnostic and management criteria of BII as in published guidance. Uncertainty exists as to the optimal diagnosis and management of differing grades of severity of BII. Future research should investigate the accuracy of bronchoscopic grading of BII, the value of bronchial lavage in differing severity groups and the effectiveness of nebulised therapies in different severities of BII.

Norepinephrine versus phenylephrine for treating hypotension during general anaesthesia in adult patients undergoing major noncardiac surgery: a multicentre, open-label, cluster-randomised, crossover, feasibility, and pilot trial.

BACKGROUND: Intraoperative hypotension is associated with postoperative complications. The use of vasopressors is often required to correct hypotension but the best vasopressor is unknown. METHODS: A multicentre, cluster-randomised, crossover, feasibility and pilot trial was conducted across five hospitals in California. Phenylephrine (PE) vs norepinephrine (NE) infusion as the first-line vasopressor in patients under general anaesthesia alternated monthly at each hospital for 6 months. The primary endpoint was first-line vasopressor administration compliance of 80% or higher. Secondary endpoints were acute kidney injury (AKI), 30-day mortality, myocardial injury after noncardiac surgery (MINS), hospital length of stay, and rehospitalisation within 30 days. RESULTS: A total of 3626 patients were enrolled over 6 months; 1809 patients were randomised in the NE group, 1817 in the PE group. Overall, 88.2% received the assigned first-line vasopressor. No drug infiltrations requiring treatment were reported in either group. Patients were median 63 yr old, 50% female, and 58% white. Randomisation in the NE group vs PE group did not reduce readmission within 30 days (adjusted odds ratio=0.92; 95% confidence interval, 0.6-1.39), 30-day mortality (1.01; 0.48-2.09), AKI (1.1; 0.92-1.31), or MINS (1.63; 0.84-3.16). CONCLUSIONS: A large and diverse population undergoing major surgery under general anaesthesia was successfully enrolled and randomised to receive NE or PE infusion. This pilot and feasibility trial was not powered for adverse postoperative outcomes and a follow-up multicentre effectiveness trial is planned. CLINICAL TRIAL REGISTRATION: NCT04789330 (ClinicalTrials.gov).

Optimizing the Design and Analysis of Future AKI Trials.

AKI is a complex clinical syndrome associated with an increased risk of morbidity and mortality, particularly in critically ill and perioperative patient populations. Most AKI clinical trials have been inconclusive, failing to detect clinically important treatment effects at predetermined statistical thresholds. Heterogeneity in the pathobiology, etiology, presentation, and clinical course of AKI remains a key challenge in successfully testing new approaches for AKI prevention and treatment. This article, derived from the "AKI" session of the "Kidney Disease Clinical Trialists" virtual workshop held in October 2021, reviews barriers to and strategies for improving the design and implementation of clinical trials in patients with, or at risk of, developing AKI. The novel approaches to trial design included in this review span adaptive trial designs that increase the knowledge gained from each trial participant; pragmatic trial designs that allow for the efficient enrollment of sufficiently large numbers of patients to detect small, but clinically significant, treatment effects; and platform trial designs that use one trial infrastructure to answer multiple clinical questions simultaneously. This review also covers novel approaches to clinical trial analysis, such as Bayesian analysis and assessing heterogeneity in the response to therapies among trial participants. We also propose a road map and actionable recommendations to facilitate the adoption of the reviewed approaches. We hope that the resulting road map will help guide future clinical trial planning, maximize learning from AKI trials, and reduce the risk of missing important signals of benefit (or harm) from trial interventions.

Digital health and artificial intelligence in kidney research: a report from the 2020 Kidney Disease Clinical Trialists (KDCT) meeting.

The exponential growth in digital technology coupled with the global coronavirus disease 2019 pandemic is driving a profound change in the delivery of medical care and research conduct. The growing availability of electronic monitoring, electronic health records, smartphones and other devices and access to ever greater computational power provides not only new opportunities, but also new challenges. Artificial intelligence (AI) exemplifies the potential of this digital revolution, which also includes other tools such as mobile health (mHealth) services and wearables. Despite digital technology becoming commonplace, its use in medicine and medical research is still in its infancy, with many clinicians and researchers having limited experience with such tools in their usual practice. This article, derived from the 'Digital Health and Artificial Intelligence' session of the Kidney Disease Clinical Trialists virtual workshop held in September 2020, aims to illustrate the breadth of applications to which digital tools and AI can be applied in clinical medicine and research. It highlights several innovative projects incorporating digital technology that range from streamlining medical care of those with acute kidney injury to the use of AI to navigate the vast genomic and proteomic data gathered in kidney disease. Important considerations relating to any new digital health project are presented, with a view to encouraging the further evolution and refinement of these new tools in a manner that fosters collaboration and the generation of robust evidence.

Pragmatic platform trials to improve the outcome of patients with acute kidney injury.

PURPOSE OF REVIEW: There is an important need for improved diagnostic strategies and treatment among patients with acute kidney injury (AKI). Classical randomized clinical trials have generated relevant results in AKI but are associated with shortcomings, such as high costs and sometimes lack of generalizability. In this minireview, we discuss the value and limits of pragmatic trials and platform trials for AKI research. RECENT FINDINGS: The implementation of pragmatic and platform trials in critical care settings has generated relevant clinical evidence impacting clinical practice. Pragmatic and platform designs have recently been applied to patients at risk of AKI and represent a crucial opportunity to advance our understanding of optimized treatment and strategies in patients at risk of AKI or presenting with AKI. Trials embedded in electronic health records can facilitate patient enrollment and data collection. Platform trials have allowed for a more efficient study design. Although both pragmatic and platform trials have several advantages, they also come with the challenges and shortcomings discussed in this review. SUMMARY: Pragmatic and platform trials can provide clinical answers in 'real-life' settings, facilitate a significant sample size enrollment at a limited cost, and provide results that can have a faster implementation in clinical practice.

Activation of CB1R Promotes Lipopolysaccharide-Induced IL-10 Secretion by Monocytic Myeloid-Derived Suppressive Cells and Reduces Acute Inflammation and Organ Injury.

Cannabis sativa and its principal components, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol, are increasingly being used to treat a variety of medical problems, including inflammatory conditions. Although studies suggest that the endocannabinoid system has immunomodulatory properties, there remains a paucity of information on the effects of cannabinoids on immunity and on outcomes of infection and injury. We investigated the effects and mechanism(s) of action of cannabinoid receptor agonists, including Δ9-THC, on inflammation and organ injury in endotoxemic mice. Administration of Δ9-THC caused a dramatic early upregulation of plasma IL-10 levels, reduced plasma IL-6 and CCL-2 levels, led to better clinical status, and attenuated organ injury in endotoxemic mice. The anti-inflammatory effects of Δ9-THC in endotoxemic mice were reversed by a cannabinoid receptor type 1 (CB1R) inverse agonist (SR141716), and by clodronate-induced myeloid-cell depletion, but not by genetic invalidation or blockade of other putative Δ9-THC receptors, including cannabinoid receptor type 2, TRPV1, GPR18, GPR55, and GPR119. Although Δ9-THC administration reduced the activation of several spleen immune cell subsets, the anti-inflammatory effects of Δ9-THC were preserved in splenectomized endotoxemic mice. Finally, using IL-10-GFP reporter mice, we showed that blood monocytic myeloid-derived suppressive cells mediate the Δ9-THC-induced early rise in circulating IL-10. These results indicate that Δ9-THC potently induces IL-10, while reducing proinflammatory cytokines, chemokines, and related organ injury in endotoxemic mice via the activation of CB1R. These data have implications for acute and chronic conditions that are driven by dysregulated inflammation, such as sepsis, and raise the possibility that CB1R-signaling may constitute a novel target for inflammatory disorders.

Fluids, vasopressors, and acute kidney injury after major abdominal surgery between 2015 and 2019: a multicentre retrospective analysis.

BACKGROUND: Practice patterns related to intraoperative fluid administration and vasopressor use have potentially evolved over recent years. However, the extent of such changes and their association with perioperative outcomes, such as the development of acute kidney injury (AKI), have not been studied. METHODS: We performed a retrospective analysis of major abdominal surgeries in adults across 26 US hospitals between 2015 and 2019. The primary outcome was AKI as defined by the Kidney Disease Improving Global Outcomes definition (KDIGO) using only serum creatinine criteria. Univariable linear predictive additive models were used to describe the dose-dependent risk of AKI given fluid administration or vasopressor use. RESULTS: Over the study period, we observed a decrease in the volume of crystalloid administered, a decrease in the proportion of patients receiving more than 10 ml kg-1 h-1 of crystalloid, an increase in the amount of norepinephrine equivalents administered, and a decreased duration of hypotension. The incidence of AKI increased between 2016 and 2019. An increase of crystalloid administration from 1 to 10 ml kg-1 h-1 was associated with a 58% decreased risk of AKI. CONCLUSIONS: Despite decreased duration of hypotension during the study period, decreased fluid administration and increased vasopressor use were associated with increased incidence of AKI. Crystalloid administration below 10 ml kg-1 h-1 was associated with an increased risk of AKI. Although no causality can be concluded, these data suggest that prevention and treatment of hypotension during abdominal surgery with liberal use of vasopressors at the expense of fluid administration is associated with an increased risk of postoperative AKI.

Capillary refill time for the management of acute circulatory failure: a survey among pediatric and adult intensivists.

INTRODUCTION: Recent studies have shown the prognostic value of capillary refill time (CRT) and suggested that resuscitation management guided by CRT may reduce morbidity and mortality in patients with septic shock. However, little is known about the current use of CRT in routine clinical practice. This study aimed to assess the modalities of CRT use among French adult and pediatric intensivists. METHODS: A cross-sectional survey exploring CRT practices in acute circulatory failure was performed. The targeted population was French adult and pediatric intensivists (SFAR and GFRUP networks). An individual invitation letter including a survey of 32 questions was emailed twice. Descriptive and analytical statistics were performed. RESULTS: Among the 6071 physicians who received the letter, 418 (7%) completed the survey. Among all respondents, 82% reported using CRT in routine clinical practice, mainly to diagnose acute circulatory failure, but 45% did not think CRT had any prognostic value. Perfusion goal-directed therapy based on CRT was viewed as likely to improve patient outcome by 37% of respondents. The measurement of CRT was not standardized as the use of a chronometer was rare (3%) and the average of multiple measurements rarely performed (46%). Compared to adult intensivists, pediatric intensivists used CRT more frequently (99% versus 76%) and were more confident in its diagnostic value and its ability to guide treatment. CONCLUSION: CRT measurement is widely used by intensivists in patients with acute circulatory failure but most often in a non-standardized way. This may lead to a misunderstanding of CRT reliability and clinical usefulness.

Galectin-3 in Kidney Diseases: From an Old Protein to a New Therapeutic Target.

Galectin-3 (Gal-3) is a 30KDa lectin implicated in multiple pathophysiology pathways including renal damage and fibrosis. Gal-3 binds ß-galactoside through its carbohydrate-recognition domain. From intra-cellular to extra-cellular localization, Gal-3 has multiple roles including transduction signal pathway, cell-to-cell adhesion, cell to extracellular matrix adhesion, and immunological chemoattractant protein. Moreover, Gal-3 has also been linked to kidney disease in both preclinical models and clinical studies. Gal-3 inhibition appears to improve renal disease in several pathological conditions, thus justifying the development of multiple drug inhibitors. This review aims to summarize the latest literature regarding Gal-3 in renal pathophysiology, from its role as a biomarker to its potential as a therapeutic agent.