Epidemiology and outcomes of early versus late septic acute kidney injury in critically ill patients: A retrospective cohort study.

BACKGROUND: It was recently proposed to distinguish early from late sepsis-associated acute kidney injury (SA-AKI). We aimed to determine the relative frequency of these entities in critically ill patients and to describe their characteristics and outcomes. METHODS: We included in this retrospective cohort study all adult patients admitted for sepsis in a tertiary ICU between 2010 and 2020. We excluded those on chronic dialysis or without consent. We extracted serum creatinine, hourly urinary output, and clinical and socio-demographic data from medical records until day 7 or ICU discharge. AKI presence and characteristics were assessed daily using KDIGO criteria. We compared patients with early (occurring within 2 days of admission) or late (occurring between day 2 and day 7) SA-AKI. We conducted sensitivity analyses using different definitions for early/late SA-AKI. RESULTS: Among 1835 patients, 1660 (90%) fulfilled SA-AKI criteria. Of those, 1610 (97%) had early SA-AKI, and 50 (3%) had late SA-AKI. Similar proportions were observed when only considering AKI with elevated sCr (71% vs. 3%), severe AKI (67% vs. 6%), or different time windows for early SA-AKI. Compared with early SA-AKI patients, those with late SA-AKI were younger (median age [IQR] 59 [49-70] vs. 69 [58-76] years, p < 0.001), had lower Charlson comorbidity index (3 [1-5] vs. 5 [3-7], p < 0.001) and lower SAPSII scores (41 [34-50] vs. 53 [43-64], p < 0.001). They had similar (24% vs. 26%, p = 0.75) in-hospital mortality. CONCLUSIONS: AKI is almost ubiquitous in septic critically ill patients and present within two days of admission. The timing from ICU admission might not be relevant to distinguish different phenotypes of SA-AKI. ETHICS APPROVAL: Ethics Committee Vaud, Lausanne, Switzerland (n°2017-00008).

Economic burden of in-hospital AKI: a one-year analysis of the nationwide French hospital discharge database.

BACKGROUND: Although Acute Kidney Injury (AKI) incidence is increasing worldwide, data investigating its cost are lacking. This population-wide study aimed to describe the characteristics and costs of hospital stays with, and without AKI, and to estimate the AKI-associated increases in costs and length of stay (LOS) in three subgroups (major open visceral surgery (MOV), cardiovascular surgery with extracorporeal circulation (CVEC), and sepsis). METHODS: All hospital stays that occurred in France in 2018 were included. Stay and patient characteristics were collected in the French hospital discharge database and described. Medical conditions were identified using the 10th International Classification of Diseases and the medical acts classification. In each subgroup, the adjusted increase in cost and LOS associated with AKI was estimated using a generalized linear model with gamma distribution and a log link function. RESULTS: 26,917,832 hospital stays, of which 415,067 (1.5%) with AKI, were included. AKI was associated with 83,553 (19.8%), 7,165 (17.9%), and 15,387 (9.2%) of the stays with sepsis, CVEC, and MOV, respectively. Compared to stays without AKI, stays with AKI were more expensive (median [IQR] €4,719[€2,963-€7782] vs. €735[€383-€1,805]) and longer (median [IQR] 9[4-16] vs. 0[0-2] days). AKI was associated with a mean [95%CI] increase in hospitalization cost of 70% [69;72], 48% [45;50], and 68% [65;70] in the sepsis, CVEC, and MOV groups respectively, after adjustment. CONCLUSION: This study confirms the major economic burden of in-hospital AKI in a developed country. Interventions to prevent AKI are urgently needed and their cost should be balanced with AKI-related costs.

Hemoperfusion in Burns.

Patients with severe thermal injury require urgent specialized care in burn units. These units assure good coordination of a bundle of care including fluid resuscitation, nutritional support, respiratory care, surgical care and wound care, infection prevention, and rehabilitation. When severely injured, burn patients present a systemic inflammatory response syndrome, associated with a dysregulated immune homeostasis. This complex host response exposes patients to prolonged hospitalization with suppressed immune function, increased susceptibility to secondary infections, longer organ support, and increased mortality. To date, several strategies, such as hemoperfusion techniques, have been developed to mitigate immune activation. We propose herein a review of the immune response to burn injury and the rationale and potential applications of extracorporeal blood purification techniques such as hemoperfusion for burn patients' management.

Identification of an optimal threshold to define oliguria in critically ill patients: an observational study.

BACKGROUND: The relevance of current consensus threshold to define oliguria has been challenged by small observational studies. We aimed to determine the optimal threshold to define oliguria in critically-ill patients. METHODS: Cohort study including adult patients admitted within a multi-disciplinary intensive care unit between January 1st 2010 and June 15th 2020. Patients on chronic dialysis or who declined consent were excluded. We extracted hourly urinary output (UO) measurements along with patient's characteristics from electronic medical records and 90-day mortality from the Swiss national death registry. We randomly split our data into a training (80%) and a validation (20%) set. In the training set, we developed multivariable models to assess the relationship between 90-day mortality and the minimum average UO calculated over time windows of 3, 6, 12 and 24 h. Optimal thresholds were determined by visually identifying cut-off values for the minimum average UO below which predicted mortality increased substantially. We tested models' discrimination and calibration on the entire validation set as well as on a subset of patients with oliguria according to proposed thresholds. RESULTS: Among the 15,500 patients included in this analysis (training set: 12,440, validation set: 3110), 73.0% (95% CI [72.3-73.8]) presented an episode of oliguria as defined by consensus criteria (UO < 0.5 ml/kg/h for 6 h). Our models had excellent (AUC > 85% for all time windows) discrimination and calibration. The relationship between minimum average UO and predicted 90-day mortality was nonlinear with an inflexion point at 0.2 ml/kg/h for 3 and 6 h windows and 0.3 ml/kg/h for 12 and 24 h windows. Considering a threshold of < 0.2 ml/kg/h over 6 h, the proportion of patients with an episode of oliguria decreased substantially to 24.7% (95% CI [24.0-25.4]). Contrary to consensus definition, this threshold identified a population with a higher predicted 90-day mortality. CONCLUSIONS: The widely used cut-off for oliguria of 0.5 ml/kg/h over 6 h may be too conservative. A cut-off of 0.2 ml/kg/h over 3 or 6 h is supported by the data and should be considered in further definitions of oliguria.

Persistently Elevated Soluble Triggering Receptor Expressed on Myeloid Cells 1 and Decreased Monocyte Human Leucocyte Antigen DR Expression Are Associated With Nosocomial Infections in Septic Shock Patients.

Sepsis-acquired immunosuppression may play a major role in patients' prognosis through increased risk of secondary infections. Triggering receptor expressed on myeloid cells 1 (TREM-1) is an innate immune receptor involved in cellular activation. Its soluble form (sTREM-1) has been described as a robust marker of mortality in sepsis. The objective of this study was to evaluate its association with the occurrence of nosocomial infections alone or in combination with human leucocyte antigen-DR on monocytes (mHLA-DR). DESIGN: Observational study. SETTING: University Hospital in France. PATIENTS: One hundred sixteen adult septic shock patients as a post hoc study from the IMMUNOSEPSIS cohort (NCT04067674). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma sTREM-1 and monocyte HLA-DR were measured at day 1 or 2 (D1/D2), D3/D4, and D6/D8 after admission. Associations with nosocomial infection were evaluated through multivariable analyses. At D6/D8, both markers were combined, and association with increased risk of nosocomial infection was evaluated in the subgroup of patients with most deregulated markers in a multivariable analysis with death as a competing risk. Significantly decreased mHLA-DR at D6/D8 and increased sTREM-1 concentrations were measured at all time points in nonsurvivors compared with survivors. Decreased mHLA-DR at D6/D8 was significantly associated with increased risk of secondary infections after adjustment for clinical parameters with a subdistribution hazard ratio of 3.61 (95% CI, 1.39-9.34; p = 0.008). At D6/D8, patients with persistently high sTREM-1 and decreased mHLA-DR presented with a significantly increased risk of infection (60%) compared with other patients (15.7%). This association remained significant in the multivariable model (subdistribution hazard ratio [95% CI], 4.65 [1.98-10.9]; p < 0.001). CONCLUSIONS: In addition to its prognostic interest on mortality, sTREM-1, when combined with mHLA-DR, may help to better identify immunosuppressed patients at risk of nosocomial infections.

Biomarker-guided intervention to prevent acute kidney injury after major surgery (BigpAK-2 trial): study protocol for an international, prospective, randomised controlled multicentre trial.

INTRODUCTION: Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation. METHODS AND ANALYSIS: The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage. ETHICS AND DISSEMINATION: The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research. TRIAL REGISTRATION NUMBER: NCT04647396.

Cytokine hemoadsorption with CytoSorb® in post-cardiac arrest syndrome, a pilot randomized controlled trial.

BACKGROUND: Hemoadsorption (HA) might mitigate the systemic inflammatory response associated with post-cardiac arrest syndrome (PCAS) and improve outcomes. Here, we investigated the feasibility, safety and efficacy of HA with CytoSorb® in cardiac arrest (CA) survivors at risk of PCAS. METHODS: In this pilot randomized controlled trial, we included patients admitted to our intensive care unit following CA and likely to develop PCAS: required norepinephrine (> 0.2 µg/kg/min), and/or had serum lactate > 6 mmol/l and/or a time-to-return of spontaneous circulation (ROSC) > 25 min. Those requiring ECMO or renal replacement therapy were excluded. Eligible patients were randomly allocated to either receive standard of care (SOC) or SOC plus HA. Hemoadsorption was performed as stand-alone therapy for 24 h, using CytoSorb® and regional heparin-protamine anticoagulation. We collected feasibility, safety and clinical data as well as serial plasma cytokines levels within 72 h of randomization. RESULTS: We enrolled 21 patients, of whom 16 (76%) had out-of-hospital CA. Median (IQR) time-to-ROSC was 30 (20, 45) minutes. Ten were assigned to the HA group and 11 to the SOC group. Hemoadsorption was initiated in all patients allocated to the HA group within 18 (11, 23) h of ICU admission and conducted for a median duration of 21 (14, 24) h. The intervention was well tolerated except for a trend for a higher rate of aPTT elevation (5 (50%) vs 2 (18%) p = 0.18) and mild (100-150 G/L) thrombocytopenia at day 1 (5 (50%) vs 2 (18%) p = 0.18). Interleukin (IL)-6 plasma levels at randomization were low (< 100 pg/mL) in 10 (48%) patients and elevated (> 1000 pg/mL) in 6 (29%). The median relative reduction in IL-6 at 48 h was 75% (60, 94) in the HA group versus 5% (- 47, 70) in the SOC group (p = 0.06). CONCLUSIONS: In CA survivors at risk of PCAS, HA was feasible, safe and was associated with a nonsignificant reduction in cytokine plasma levels. Future trials are needed to further define the role of HA after CA. Those studies should include cytokine assessment to enrich the study population. TRIAL REGISTRATION: NCT03523039, registered 14 May 2018.

Extracorporeal Blood Purification in Burns: For Whom, Why, and How?

Patients with serious thermal burn injuries require immediate and specialized care in order to minimize morbidity and mortality. Optimal fluid resuscitation, nutritional support, pulmonary care, burn wound care, and infection control practices represent key aspects of patient care in burn centers. When severely burned, the patient usually presents a systemic inflammatory response syndrome, soon balanced by a counter anti-inflammatory response syndrome. These may lead to immune dysregulation/exhaustion favoring infectious complications that dramatically impair the prognosis of burn patients. This narrative review provides an overview of the main concepts, current understanding, and potential applications of extracorporeal blood purification techniques for burn patient management. Current understanding of burn patients' immune responses is reported. Hypotheses and data on the potential value of immunoregulation are reviewed. Finally, how extracorporeal blood purification may be of interest in this specific population is discussed.

New Targets for Extracorporeal Blood Purification Therapies in Sepsis.

As highlighted by the last international consensus definition for sepsis and septic shock (sepsis-3), sepsis comes from a complex relationship between a pathogen and a dysregulated host response. To date, the treatment of sepsis is based on antimicrobial treatment, source control, and organ support. Extracorporeal blood purification therapies have been proposed as adjuvant therapies to modulate the dysregulated inflammatory response. These therapies aim mostly at removing inflammatory mediators (cytokines) and endotoxins from the blood. However, so far, they failed to clearly demonstrate an improvement in patient survival when evaluated in randomized trials. Recently, new devices directly targeting the primary determinants of sepsis, e.g., the pathogen itself and the host immune cells, have been developed. This short review aimed at presenting new blood purification devices that have recently been developed to target pathogens and immune cells. For each, we will present the mechanism of action of the therapy and discuss the related literature.

A 9-mRNA signature measured from whole blood by a prototype PCR panel predicts 28-day mortality upon admission of critically ill COVID-19 patients.

Immune responses affiliated with COVID-19 severity have been characterized and associated with deleterious outcomes. These approaches were mainly based on research tools not usable in routine clinical practice at the bedside. We observed that a multiplex transcriptomic panel prototype termed Immune Profiling Panel (IPP) could capture the dysregulation of immune responses of ICU COVID-19 patients at admission. Nine transcripts were associated with mortality in univariate analysis and this 9-mRNA signature remained significantly associated with mortality in a multivariate analysis that included age, SOFA and Charlson scores. Using a machine learning model with these 9 mRNA, we could predict the 28-day survival status with an Area Under the Receiver Operating Curve (AUROC) of 0.764. Interestingly, adding patients' age to the model resulted in increased performance to predict the 28-day mortality (AUROC reaching 0.839). This prototype IPP demonstrated that such a tool, upon clinical/analytical validation and clearance by regulatory agencies could be used in clinical routine settings to quickly identify patients with higher risk of death requiring thus early aggressive intensive care.

Trends in the proportion of resistant bacteria involved in ventilator-associated pneumonia as the first hospital-acquired infection in intensive care units between 2003 and 2016 in Lyon, France.

The aim of this study was to describe the proportion of multidrug-resistant microorganisms (MDROs) involved in ventilator-associated pneumonia (VAP) as the first hospital-acquired infection in 536 adults with restricted risk factors for MDRO-related infection. We found a significant decrease in the percentage of MDROs involved in VAP between 2003 and 2016 and this percentage increased when VAP occurred after day 10.

Longitudinal assessment of IFN-I activity and immune profile in critically ill COVID-19 patients with acute respiratory distress syndrome.

BACKGROUND: Since the onset of the pandemic, only few studies focused on longitudinal immune monitoring in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) whereas their hospital stay may last for several weeks. Consequently, the question of whether immune parameters may drive or associate with delayed unfavorable outcome in these critically ill patients remains unsolved. METHODS: We present a dynamic description of immuno-inflammatory derangements in 64 critically ill COVID-19 patients including plasma IFNα2 levels and IFN-stimulated genes (ISG) score measurements. RESULTS: ARDS patients presented with persistently decreased lymphocyte count and mHLA-DR expression and increased cytokine levels. Type-I IFN response was initially induced with elevation of IFNα2 levels and ISG score followed by a rapid decrease over time. Survivors and non-survivors presented with apparent common immune responses over the first 3 weeks after ICU admission mixing gradual return to normal values of cellular markers and progressive decrease of cytokines levels including IFNα2. Only plasma TNF-α presented with a slow increase over time and higher values in non-survivors compared with survivors. This paralleled with an extremely high occurrence of secondary infections in COVID-19 patients with ARDS. CONCLUSIONS: Occurrence of ARDS in response to SARS-CoV2 infection appears to be strongly associated with the intensity of immune alterations upon ICU admission of COVID-19 patients. In these critically ill patients, immune profile presents with similarities with the delayed step of immunosuppression described in bacterial sepsis.

[Study of monocytic myeloid-derived suppressor cells and CD4 lymphopenia in septic shock-induced immunosuppression]. / Étude des cellules myéloïdes immunosuppressives monocytaires au cours de l'immunodépression associée au choc septique.

Sepsis is one of the leading causes of in-hospital mortality. In some patients, sepsis-induced immunosuppression is associated with increased risk of death and secondary infections. In oncology, myeloid-derived suppressor cells (MDSCs) have been described to inhibit various immune functions. Monocytic MDSCs (M-MDSCs) represent a subtype of MDSCs. The objectives of the present study was to determine by flow cytometry the % M-MDSCs (among total monocyte population) in a cohort of septic shock patients and to assess its association with deleterious outcomes: 28-day mortality and occurrence of nosocomial infections. The cohort included 301 patients. They presented with immune alterations usually found 3-4 days after the onset of shock: lymphopenia (median T CD4: 362/µL, quartiles: 235-591/µL) and low monocytic HLA-DR expression (median: 4,944 AB/C, quartiles: 3,104-8,266 AB/C). From admission until the end of the first week, % M-MDSCs was significantly increased in patients compared with healthy donors (p < 0.01). In early samples, no association with deleterious outcomes was identified. However, after one week, patients who were going to die or to develop nosocomial infections presented with significantly higher % M-MDSCs than non-survivors and non-infected patients (p < 0.01). These associations remained significant in multivariate analyses, odds ratio of 4.4 (p = 0.001) regarding 28-day mortality and 2.4 (p = 0.013) regarding occurrence of nosocomial infections. In conclusion, % M-MDSCs was markedly increased after septic shock. One week-persistence of an increased proportion of M-MDSCs was associated with unfavorable outcomes.

Implementation of French Recommendations for the Prevention and the Treatment of Hospital-acquired Pneumonia: A Cluster-randomized Trial.

BACKGROUND: We determined whether an audit on the adherence to guidelines for hospital-acquired pneumonia (HAP) can improve the outcomes of patients in intensive care units (ICUs). METHODS: This study was conducted at 35 ICUs in 30 hospitals. We included consecutive, adult patients hospitalized in ICUs for 3 days or more. After a 3-month baseline period followed by the dissemination of recommendations, an audit on the compliance to recommendations (audit period) was followed by a 3-month cluster-randomized trial. We randomly assigned ICUs to either receive audit and feedback (intervention group) or participate in a national registry (control group). The primary outcome was the duration of ICU stay. RESULTS: Among 1856 patients enrolled, 602, 669, and 585 were recruited in the baseline, audit, and intervention periods, respectively. The composite measures of compliance were 47% (interquartile range [IQR], 38-56%) in the intervention group and 42% (IQR, 25-53%) in the control group (P = .001). As compared to the baseline period, the ICU lengths of stay were reduced by 3.2 days in the intervention period (P = .07) and by 2.8 days in the control period (P = .02). The durations of ICU stay were 7 days (IQR, 5-14 days) in the control group and 9 days (IQR, 5-20 days) in the intervention group (P = .10). After adjustment for unbalanced baseline characteristics, the hazard ratio for being discharged alive from the ICU in the control group was 1.17 (95% confidence interval, .69-2.01; P = .10). CONCLUSIONS: The publication of French guidelines for HAP was associated with a reduction of the ICU length of stay. However, the realization of an audit to improve their application did not further improve outcomes. CLINICAL TRIALS REGISTRATION: NCT03348579.

Multicenter evaluation of a syndromic rapid multiplex PCR test for early adaptation of antimicrobial therapy in adult patients with pneumonia.

BACKGROUND: Improving timeliness of pathogen identification is crucial to allow early adaptation of antibiotic therapy and improve prognosis in patients with pneumonia. We evaluated the relevance of a new syndromic rapid multiplex PCR test (rm-PCR) on respiratory samples to guide empirical antimicrobial therapy in adult patients with community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and ventilator-acquired pneumonia (VAP). METHODS: This retrospective multicenter study was conducted in four French university hospitals. Respiratory samples were obtained from patients with clinical and radiological signs of pneumonia and simultaneously tested using conventional microbiological methods and the rm-PCR. A committee composed of an intensivist, a microbiologist, and an infectious diseases specialist retrospectively assessed all medical files and agreed on the most appropriate antimicrobial therapy for each pneumonia episode, according to the results of rm-PCR and blinded to the culture results. The rm-PCR-guided antimicrobial regimen was compared to the empirical treatment routinely administered to the patient in standard care. RESULTS: We included 159 pneumonia episodes. Most patients were hospitalized in intensive care units (n = 129, 81%), and episodes were HAP (n = 68, 43%), CAP (n = 54, 34%), and VAP (n = 37, 23%). Conventional culture isolated ≥ 1 microorganism(s) at significant level in 95 (60%) patients. The syndromic rm-PCR detected at least one bacteria in 132 (83%) episodes. Based on the results of the rm-PCR, the multidisciplinary committee proposed a modification of the empirical therapy in 123 (77%) pneumonia episodes. The modification was a de-escalation in 63 (40%), an escalation in 35 (22%), and undetermined in 25 (16%) patients. In microbiologically documented episodes (n = 95), the rm-PCR increased appropriateness of the empirical therapy to 83 (87%), as compared to 73 (77%) in routine care. CONCLUSIONS: Use of a syndromic rm-PCR test has the potential to reduce unnecessary antimicrobial exposure and increase the appropriateness of empirical antibiotic therapy in adult patients with pneumonia.