Modifiability of surgical timing in postinjury multiple organ failure patients.

BACKGROUND: Postinjury multiple organ failure (MOF) is the leading cause of late trauma deaths, with primarily non-modifiable risk factors. Timing of surgery as a potentially modifiable risk factor is frequently proposed, but has not been quantified. We aimed to compare mortality, hospital length of stay (LOS), and ICU LOS between MOF patients who had surgery that preceded MOF with modifiable timings versus those with non-modifiable timings. METHODS: Retrospective analysis of an ongoing 17-year prospective cohort study of ICU polytrauma patients at-risk of MOF. Among MOF patients (Denver score>3), we identified patients who had surgery that preceded MOF, determined whether the timing of these operation(s) were modifiable(M) or non-modifiable (non-M), and evaluated the change in physiological parameters as a result of surgery. RESULTS: Of 716 polytrauma patients at-risk of MOF, 205/716 (29%) developed MOF, and 161/205 (79%) had surgery during their ICU admission. Of the surgical MOF patients, 147/161 (91%) had one or more operation(s) that preceded MOF, and 65/161 (40%) of them had operation(s) with modifiable timings. There were no differences in age (mean (SD) 52 (19) vs 53 (21)years), injury severity score (median (IQR) 34 (26-41)vs34 (25-44)), admission physiological and resuscitation parameters, between M and non-M-patients. M patients had longer ICU LOS (median (IQR) 18 (12-28)versus 11 (8-16)days, p < 0.0001) than non-M-patients, without difference in mortality (14%vs16%, p = 0.7347), or hospital LOS (median (IQR) 32 (18-52)vs27 (17-47)days, p = 0.3418). M-patients had less fluids and transfusions intraoperatively. Surgery did not compromise patient physiology. CONCLUSION: Operations preceding MOF are common in polytrauma and seem to be safe in maintaining physiology. The margin for improvement from optimizing surgical timing is modest, contrary to historical assumptions.

Population sepsis incidence, mortality, and trends in Hong Kong between 2009-2018 using clinical and administrative data.

BACKGROUND: Sepsis surveillance using electronic health record (EHR)-based data may provide more accurate epidemiologic estimates than administrative data, but experience with this approach to estimate population-level sepsis burden is lacking. METHODS: This was a retrospective cohort study including all adults admitted to publicly-funded hospitals in Hong Kong between 2009-2018. Sepsis was defined as clinical evidence of presumed infection (clinical cultures and treatment with antibiotics) and concurrent acute organ dysfunction (≥2 point increase in baseline SOFA score). Trends in incidence, mortality, and case fatality risk (CFR) were modelled by exponential regression. Performance of the EHR-based definition was compared with 4 administrative definitions using 500 medical record reviews. RESULTS: Among 13,550,168 hospital episodes during the study period, 485,057 (3.6%) had sepsis by EHR-based criteria with 21.5% CFR. In 2018, age- and sex-adjusted standardized sepsis incidence was 759 per 100,000 (relative +2.9%/year [95%CI 2.0, 3.8%] between 2009-2018) and standardized sepsis mortality was 156 per 100,000 (relative +1.9%/year [95%CI 0.9,2.9%]). Despite decreasing CFR (relative -0.5%/year [95%CI -1.0, -0.1%]), sepsis accounted for an increasing proportion of all deaths (relative +3.9%/year [95%CI 2.9, 4.9%]). Medical record reviews demonstrated that the EHR-based definition more accurately identified sepsis than administrative definitions (AUC 0.91 vs 0.52-0.55, p < 0.001). CONCLUSIONS: An objective EHR-based surveillance definition demonstrated an increase in population-level standardized sepsis incidence and mortality in Hong Kong between 2009-2018 and was much more accurate than administrative definitions. These findings demonstrate the feasibility and advantages of an EHR-based approach for widescale sepsis surveillance.

Characterization of multiple organ failure after ruptured abdominal aortic aneurysm repair.

BACKGROUND: Multiple organ failure (MOF) is associated with poor outcomes and increased mortality in sepsis and trauma. There are limited data regarding MOF in patients after ruptured abdominal aortic aneurysm (rAAA) repair. We aimed to identify the contemporary prevalence and characteristics of patients with rAAA with MOF. METHODS: We retrospectively reviewed patients with rAAA who underwent repair (2010-2020) at our multihospital institution. Patients who died within the first 2 days after repair were excluded. MOF was quantified by modified (excluding hepatic system) Denver, Sequential Organ Failure Assessment (SOFA) score, and Multiple Organ Dysfunction Score (MODS) for postoperative days 3 to 5 to determine the prevalence of MOF. MOF was defined as a Denver score of >3, dysfunction in two or more organ systems by SOFA score, or a MODS score of >8. Kaplan-Meier curves and log-rank testing were used to evaluate differences in 30-day mortality between multiple organ failure and patients without MOF. Logistic regression was used to assess predictors of MOF. RESULTS: Of 370 patients with rAAA, 288 survived past two days (mean age, 73±10.1 years; 76.7% male; 44.1% open repair), and 143 had data for MOF calculation recorded. From postoperative days 3 to 5, 41 (14.24%) had MOF by Denver, 26 (9.03%) by SOFA, and 39 (13.54%) by MODS criteria. Among these scoring systems, pulmonary and neurological systems were impacted most commonly. Among patients with MOF, pulmonary derangement occurred in 65.9% (Denver), 57.7% (SOFA), and 56.4% (MODS). Similarly, neurological derangement occurred in 92.3% (SOFA) and 89.7% (MODS), but renal derangement occurred in 26.8% (Denver), 23.1% (SOFA), and 10.3% (MODS). MOF by all three scoring systems was associated with increased 30-day mortality (Denver: 11.3% vs 41.5% [P < .01]; DOFA: 12.6% vs 46.2% [P < .01]; MODS: 12.5% vs 35.9% [P < .01]), as was MOF by any criteria (10.8% vs 35.7 %; P < .01). Patients with MOF were more likely to have a higher body mass index (55.9±26.6 vs 49.0±15.0; P = .011) and to have had a preoperative stroke (17.9% vs 6.0%; P = .016). Patients with MOF were less likely to have undergone endovascular repair (30.4% vs 62.1%; P < .001). Endovascular repair was protective against MOF (any criteria) on multivariate analysis (odds ratio, 0.23; 95% confidence interval, 0.08-0.64; P = .019) after adjusting for age, gender, and presenting systolic blood pressure. CONCLUSIONS: MOF occurred in only 9% to 14% of patients after rAAA repair, but was associated with a three-fold increase in mortality. Endovascular repair was associated with a reduced MOF incidence.

TREM-1 as a Marker of Multiple Organ Failure in Cardiac Surgery.

Systemic inflammatory response syndrome (SIRS) frequently accompanies early postoperative period after cardiac surgery and in some cases is complicated by multiple organ failure (MOF). Inherited variation in the innate immune response genes (e.g., TREM1) is among the major factors determining the development of SIRS and the risk of MOF. This research was aimed to study whether the polymorphisms within the TREM1 gene are associated with MOF after the coronary artery bypass graft (CABG) surgery. Here we enrolled 592 patients who underwent CABG surgery in the Research Institute for Complex Issues of Cardiovascular Diseases (Kemerovo, Russia) and documented 28 cases of MOF. Genotyping was performed by allele-specific PCR using TaqMan probes. In addition, we measured serum soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) using enzyme-linked immunosorbent assay. Five polymorphisms (rs1817537, rs2234246, rs3804277, rs7768162 andrs4711668) within the TREM1 gene were significantly associated with MOF. Patients with MOF had higher serum sTREM-1 as compared with those without MOF at both pre- and post-intervention stages. Serum sTREM-1 was associated with the rs1817537,rs2234246 and rs3804277 polymorphisms within the TREM1 gene. Minor alleles within the TREM1 gene define the level of serum sTREM-1 and are associated with MOF after CABG surgery.

Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis.

BACKGROUND: One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. METHODS: We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. RESULTS: Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1ß, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1ß, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. CONCLUSIONS: These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.

Toxic shock like syndrome caused by Streptococcus agalactiae bacteremia during treatment for multiple myeloma.

Toxic shock-like syndrome (TSLS) is a life-threatening hyperinflammatory complication caused by Streptococcus species infections. We reported the first case of TSLS caused by primary bacteremia of Streptococcus agalactiae during chemotherapy for multiple myeloma. A 74-year-old woman, who received combination chemotherapy of elotuzumab, pomalidomide, and dexamethasone for treatment-refractory multiple myeloma, was transported to our hospital under comatose and septic shock. Her blood culture detected Streptococcus agalactiae, and considering the progressive multiorgan failure, she was diagnosed with TSLS. Empiric antibiotic treatment with meropenem and respiratory and circulatory support were quickly initiated, resulting in an almost complete recovery of organ functions. It should be noted that with the advances of chemotherapy, the risk of infection is becoming more diverse.

Effect of glucocorticoid for patients with type A aortic dissection undergoing surgical repair with deep hypothermic circulatory arrest: A single-center, retrospective study.

BACKGROUND: Postoperative patients with Type A aortic dissection (TAAD) often experience severe inflammatory responses caused by multiple factors perioperatively. However, the effect of postoperative glucocorticoid (GC) use, which is a potent anti-inflammatory agent, on complications or all-cause mortality is unclear. METHODS: Patients with TAAD who underwent surgical repair requiring deep hypothermic circulatory arrest between January 2020 and December 2021 were included in the study. Characteristics of patients treated with and without GCs were compared. The primary outcome was in-hospital mortality, and a composite secondary outcome was defined as in-hospital death or any major complications. Propensity score matching was used to balance baseline differences between groups. Kaplan-Meier curves were used to compare survival probability. RESULTS: A total of 393 postoperative patients with TAAD were included in the study. Forty of them (10.2%) received GC treatment at a median daily methylprednisolone-equivalent dose of 0.6 mg/kg (0.4-0.7) for a median period of 2 (1-3) days. Patients on GCs had more intraoperative blood transfusions, higher postoperative APACHE II (12 vs 9, p = .004) and SOFA (9 vs 6, p < .001) scores, worse perioperative hepatic, renal and cardiac function. The in-hospital mortality in the matched cohort did not differ between groups [GC n = 11/40 (27.5%) versus Non-GC n = 19/80 (23.8%); p = .661]. CONCLUSIONS: The propensity to use GCs correlated with the critical status of the patient. However, low dose and short-term postoperative GC treatment did not reduce in-hospital mortality rates among patients with TAAD. A more appropriate regimen should be further investigated.

Mineralocorticoid Receptor Antagonism Attenuates Multiple Organ Failure after Renal Ischemia and Reperfusion in Mice.

Renal ischemia reperfusion (IR) injury is a major cause of acute kidney injury (AKI) that is often complicated by multiple organ failure of the liver and intestine. The mineralocorticoid receptor (MR) is activated in patients with renal failure associated with glomerular and tubular damage. We thus investigated whether canrenoic acid (CA), a mineralocorticoid receptor (MR) antagonist, protects against AKI-induced hepatic and intestinal injury, suggesting the underlying mechanisms. Mice were divided into five groups: sham mice, mice subjected to renal IR, and mice pretreated with canrenoic acid (CA; 1 or 10 mg/kg) 30 min prior to renal IR. At 24 h after renal IR, the levels of plasma creatinine, alanine aminotransferase and aldosterone were measured, and structural changes and inflammatory responses of the kidney, liver, and intestine were analyzed. We found that CA treatment reduced plasma creatinine levels, tubular cell death and oxidative stress induced by renal IR. CA treatment also decreased renal neutrophil infiltration and inflammatory cytokine expression and inhibited the release of high-mobility group box 1 induced by renal IR. Consistently, CA treatment reduced renal IR-induced plasma alanine transaminase, hepatocellular injury and neutrophil infiltration, and inflammatory cytokine expression. CA treatment also decreased small intestinal cell death, neutrophil infiltration and inflammatory cytokine expression induced by renal IR. Taken together, we conclude that MR antagonism by CA treatment protects against multiple organ failure in the liver and intestine after renal IR.

[Myocardial injury in patients of the intensive care unit of various age groups.]

The article deals with the problem of myocardial damage of various genesis in patients of the intensive care unit and intensive care unit of various age groups. The study included patients with various pathologies with significant manifestations of multiple organ failure and high risks of adverse outcomes. Parametric (Student's t-test) and nonparametric (Mann-Whitney U-test, Pearson's χ2 criterion) statistical methods were used to analyze the severity of the inflammatory response, organ dysfunction, and the need for replacement therapy, in particular ventilator and vasopressor support in patients of different age groups. The frequency of myocardial damage was studied on the basis of an increase in cardiac troponin in patients of the intensive care unit. A comparison of the increase in troponin with morphological changes of the heart was carried out based on the analysis of ECHO, coronary angiography and sectional material. The role of cardiac troponin in the prognosis of adverse events in patients of different ages was analyzed. As a result of the study, it was found that the degree of severity of organ dysfunction, inflammatory response and the need for replacement therapy significantly prevail in elderly patients, as well as the phenomenon of myocardial damage. The main proportion of myocardial lesions was nonspecific. At the same time, the very fact of an increase in cardiac troponin in patients of the intensive care unit is an independent risk factor for adverse outcomes, regardless of the age of the patients.

An inquiry into the treatment of sepsis using plasma exchange therapy: A systematic review and meta-analysis.

Sepsis is a potentially lethal condition that occurs when the body's response to infection damages tissue and organs. The production of inflammatory mediators typically assists in defending the body against infection; however, an overreaction to inflammation can cause coagulation problems, vascular endothelial damage, and organ hypoperfusion. Blood purification methods, such as plasmapheresis, can effectively remove inflammatory mediators from plasma. The purpose of this meta-analysis was to explore the efficacy of plasma exchange for sepsis treatment as noted in recent studies. The authors searched the Pubmed (Medline), Cochrane Central Register of Controlled Trials (The Cochrane Library), Embase (Ovid), and Scopus databases and included controlled clinical studies that compared plasmapheresis or plasma filtration with conventional treatment in patients with severe sepsis. The Newcastle-Ottawa Scale literature quality assessment tool was used to assess the risk of bias. The primary study outcome was all-cause mortality. The random effects model was adopted for conducting the meta-analysis. Among the 1013 records found, the study included 5 trials, all of which carried a low risk of bias. The use of plasmapheresis was associated with a longer stay in the intensive care unit (odds ratio [OR], 0.85, 95% confidence interval [CI], 0.39-1.32, heterogeneity [I2 ] = 0%), a significant reduction in all-cause mortality (OR, 0.54, 95% CI, 0.33-0.89, I2  = 70%), and reduced mortality (OR, 0.29, 95% CI, 0.13-0.67, I2  = 0%) in adults; the results for children differed from this (OR, 0.79, 95% CI, 0.36-1.72, I2  = 89%). Four trials reported no adverse events; one trial reported an adverse event related to plasma exchange, including an instance of hypotension in one patient. Plasmapheresis appeared to be an effective treatment for patients suffering from sepsis. A large number of additional randomised controlled trials are needed to confirm this finding.

Pathological Changes and Cause of Death Associated with the Global Novel Coronavirus Disease (COVID-19).

The coronavirus disease 2019 (COVID-19) has been a global epidemic for more than three years, causing more than 6.9 million deaths. COVID-19 has the clinical characteristics of strong infectivity and long incubation period, and can cause multi-system damage, mainly lung damage, clinical symptoms of acute respiratory distress syndrome (ARDS) and systemic multiple organ damage. The SARS-CoV-2 virus is still constantly mutating. At present, there is no global consensus on the pathological changes of COVID-19 associated deaths and even no consensus on the criteria for determining the cause of death. The investigation of the basic pathological changes and progression of the disease is helpful to guide the clinical treatment and the development of therapeutic drugs. This paper reviews the autopsy reports and related literature published worldwide from February 2020 to June 2023, with a clear number of autopsy cases and corresponding pathological changes of vital organs as the inclusion criteria. A total of 1 111 autopsy cases from 65 papers in 18 countries are included. Pathological manifestations and causes of death are classified and statistically analyzed, common pathological changes of COVID-19 are summarized, and analytical conclusions are drawn, suggesting that COVID-19 infection can cause life-threatening pathological changes in vital organs. On the basis of different health levels of infected groups, the direct cause of death is mainly severe lung damage and secondary systemic multiple organ failure.

Role of toll-like receptors in modulation of cytokine storm signaling in SARS-CoV-2-induced COVID-19.

Balanced immune regulation is crucial for recognizing an invading pathogen, its killing, and elimination. Toll-like receptors (TLRs) are the key regulators of the innate immune system. It helps in identifying between self and nonself-molecule and eventually eliminates the nonself. Endosomal TLR, mainly TLR3, TLR7, TLR8, and membrane-bound TLR4, has a role in the induction of cytokine storms. TLR7/8 recognizes the ssRNA SARS-COV-2 and when it replicates to dsRNA, it is recognized by TLR3 and drives the TRIF-mediated inflammatory signaling like NF-κB, MAPK. Such signaling leads to significant transcription and translation of pro-inflammatory genes, releasing inflammatory molecules into the systemic circulation, causing an imbalance in the system. So, whenever an imbalance occurs, a surge in the pro-inflammatory mediators is observed in the blood, including cytokines like interleukin (IL)-2, IL-4, IL-6, IL-1ß, IL-8, interferon (IFN)-γ, tumor necrosis factor (TNF)-α. IL-6 and IL-1ß are one of the driving factors for bringing the cytokine storm into the systemic circulation, which migrates into the other organs, causing multiple organ failures leading to the death of the individual with severe illness.

Impact of carbapenem-resistant Acinetobacter baumannii infections on acute pancreatitis patients.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) infections present great challenges in clinical practices with high mortality. The aim of this study is to identify the impact of CRAB infections on acute pancreatitis (AP). METHODS: A case-control study was performed via collecting data from March 1st, 2016 to August 1st, 2020 in two comprehensive teaching hospital. Clinical data of the CRAB-positive AP patients were analyzed and compared to a matched control group (case-control ratio of 1:1). Comparisons were preformed between with/without CRAB infections and multiple organ failure (MOF), respectively. Independent risk factors of overall mortality were determined via univariate and multivariate analyses. RESULTS: CRAB infections were associated with higher mortality (49.2% vs. 23.0%, P < 0.01). CRAB combined with MOF increased a mortality up to 90% (P < 0.01). MOF (Odds ratio (OR) = 21.49, 95% confidence interval (CI) = 5.26-87.80, P < 0.01), CRAB infections (OR = 3.58, 95%CI = 1.24-10.37, P = 0.02) and hemorrhage (OR = 3.70, 95%CI = 1.21-11.28, P = 0.02) were independent risk factors of overall mortality. Lung was the most common site of strains (37 of 82). CRAB strains were highly resistant (>60%) to ten of eleven common antibiotics, except for tigecycline (28%). CONCLUSION: High mortality rate in AP patients was associated with CRAB infections and further increased when CRAB infections combined with MOF.

Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials.

BACKGROUND: Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions. METHODS: We applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin. RESULTS: Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p < 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p < 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p < 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p < 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83-136.83], p < 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26-137.75], p < 0.0001). CONCLUSIONS: Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership ( www.pedsepsis.pitt.edu ) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.

Stress response during early sedation with dexmedetomidine compared with usual-care in ventilated critically ill patients.

BACKGROUND: Sedative agents may variably impact the stress response. Dexmedetomidine is a sympatholytic alpha2-adrenergic agonist mainly used as a second-line sedative agent in mechanically ventilated patients. We hypothesised that early sedation with dexmedetomidine as the primary agent would result in a reduced stress response compared to usual sedatives in critically ill ventilated adults. METHODS: This was a prospective sub-study nested within a multi-centre randomised controlled trial of early sedation with dexmedetomidine versus usual care. The primary outcome was the mean group differences in plasma levels of stress response biomarkers measured over 5 days following randomisation. Other hormonal, biological and physiological parameters were collected. Subgroup analyses were planned for patients with proven or suspected sepsis. RESULTS: One hundred and three patients were included in the final analysis. Baseline illness severity (APACHE II score), the proportion of patients receiving propofol and the median dose of propofol received were comparable between groups. More of the usual-care patients received midazolam (57.7% vs 33.3%; p = 0.01) and at higher dose (median (95% interquartile range) 0.46 [0.20-0.93] vs 0.14 [0.08-0.38] mg/kg/day; p < 0.01). The geometric mean (95% CI) plasma level of the stress hormones, adrenaline (0.32 [0.26-0.4] vs 0.38 [0.31-0.48]), noradrenaline (4.27 [3.12-5.85] vs 6.2 [4.6-8.5]), adrenocorticotropic hormone (17.1 [15.1-19.5] vs 18.1 [15.9-20.5]) and cortisol (515 [409-648] vs 618 [491-776)] did not differ between dexmedetomidine and usual-care groups, respectively. There were no significant differences in any other assayed biomarkers or physiological parameters Sensitivity analyses showed no effect of age or sepsis. CONCLUSIONS: Early sedation with dexmedetomidine as the primary sedative agent in mechanically ventilated critically ill adults resulted in comparable changes in physiological and blood-borne parameters associated with the stress-response as with usual-care sedation.

Critical care hepatology: definitions, incidence, prognosis and role of liver failure in critically ill patients.

Organ dysfunction or overt failure is a commonplace event in the critically ill affecting up to 70% of patients during their stay in the ICU. The outcome depends on the resolution of impaired organ function, while a domino-like deterioration of organs other than the primarily affected ones paves the way for increased mortality. "Acute Liver Failure" was defined in the 1970s as a rare and potentially reversible severe liver injury in the absence of prior liver disease with hepatic encephalopathy occurring within 8 weeks. Dysfunction of the liver in general reflects a critical event in "Multiple Organ Dysfunction Syndrome" due to immunologic, regulatory and metabolic functions of liver parenchymal and non-parenchymal cells. Dysregulation of the inflammatory response, persistent microcirculatory (hypoxic) impairment or drug-induced liver injury are leading problems that result in "secondary liver failure," i.e., acquired liver injury without underlying liver disease or deterioration of preexisting (chronic) liver disease ("Acute-on-Chronic Liver Failure"). Conventional laboratory markers, such as transaminases or bilirubin, are limited to provide insight into the complex facets of metabolic and immunologic liver dysfunction. Furthermore, inhomogeneous definitions of these entities lead to widely ranging estimates of incidence. In the present work, we review the different definitions to improve the understanding of liver dysfunction as a perpetrator (and therapeutic target) of multiple organ dysfunction syndrome in critical care.

Diagnostic criteria for acute-on-chronic liver failure and related disease conditions in Japan.

The Intractable Hepato-Biliary Disease Study Group of Japan, sponsored by the Ministry of Health, Labor and Wealth, proposed in 2018 that patients with cirrhosis and a Child-Pugh score of 5-9 should be diagnosed as having acute-on-chronic liver failure (ACLF) when a deterioration of liver function ("serum bilirubin level of 5.0 mg/dl or more" and "prothrombin time value of 40% or less of the standardized values and/or international normalization rates of 1.5 or more") caused by severe liver damage develops within 28 days after an acute insult, including alcohol abuse, bacterial infection, gastrointestinal bleeding, and the exacerbation of underlying liver diseases. Disease severity can be classified into 4 grades depending on the extent of the deterioration in organ functions, including liver, kidney, cerebral, blood coagulation, circulatory and respiratory functions. The Study Group has since performed an annual nationwide survey of patients with ACLF diagnosed according to the proposed diagnostic criteria as well as those with disease conditions related to ACLF. A total of 501 patients, including 183 patients diagnosed as having ACLF, seen between 2017 and 2019 were enrolled, and univariate and multivariate analyses revealed that the proposed diagnostic criteria were useful for identifying cirrhotic patients with an unfavorable outcome following an acute insult. Consequently, the Study Group determined that the proposed diagnostic criteria should be used in both clinical practice and clinical research as formal diagnostic criteria.

The role of the ADVanced Organ Support (ADVOS) system in critically ill patients with multiple organ failure.

BACKGROUND: Multi-organ failure characterized by acute kidney injury, liver dysfunction, and respiratory failure is a complex condition associated with high mortality, for which multiple individual support devices may be simultaneously required. This review aims to appraise the current evidence for the ADVanced Organ Support (ADVOS) system, a novel device integrating liver, lung, and kidney support with blood detoxification. METHODS: We performed a literature review of the PubMed database to identify human and animal studies evaluating the ADVOS system. RESULTS: In porcine models of acute liver injury and small clinical studies in humans, ADVOS significantly enhanced the elimination of water-soluble and protein-bound toxins and metabolites, including creatinine, ammonia, blood urea nitrogen, and lactate. Cardiovascular parameters (mean arterial pressure, cerebral perfusion pressure, and cardiac index) and renal function were improved. ADVOS clears carbon dioxide (CO2 ) effectively with rapid correction of pH abnormalities, achieving normalization of CO2 , and bicarbonate levels. In patients with COVID-19 infection, ADVOS enables rapid correction of acid-base disturbance and respiratory acidosis. ADVOS therapy reduces mortality in multi-organ failure and has been shown to be safe with minimal adverse events. CONCLUSIONS: From the small observational studies analyzed, ADVOS demonstrates excellent detoxification of water-soluble and protein-bound substances. In particular, ADVOS permits the correction of metabolic and respiratory acidosis through the fluid-based direct removal of acid and CO2 . ADVOS is associated with significant improvements in hemodynamic and biochemical parameters, a trend toward improved survival in multi-organ failure, and is well-tolerated. Larger randomized trials are now necessary to further validate these encouraging results.

Janus face of complement-driven neutrophil activation during sepsis.

During local and systemic inflammation, the complement system and neutrophil granulocytes are activated not only by pathogens, but also by released endogenous danger signals. It is recognized increasingly that complement-mediated neutrophil activation plays an ambivalent role in sepsis pathophysiology. According to the current definition, the onset of organ dysfunction is a hallmark of sepsis. The preceding organ damage can be caused by excessive complement activation and neutrophil actions against the host, resulting in bystander injury of healthy tissue. However, in contrast, persistent and overwhelming inflammation also leads to a reduction in neutrophil responsiveness as well as complement components and thus may render patients at enhanced risk of spreading infection. This review provides an overview on the molecular and cellular processes that link complement with the two-faced functional alterations of neutrophils in sepsis. Finally, we describe novel tools to modulate this interplay beneficially in order to improve outcome.

Critically ill patients with severe infections related to Geotrichum species: A French retrospective multicentre study.

OBJECTIVES: Geotrichum spp can be responsible for severe infections in immunocompromised patients. We aim to describe Geotrichum-related infections in the ICU and to assess risk factors of mortality. METHODS: Retrospective multicentre study, conducted in 14 French ICUs between 2002 and 2018, including critically ill adult patients with proven or probable infection related to Geotrichum species. Data were obtained from the medical charts. RESULTS: Thirty-six patients, median age 60 years IQR [53; 66] were included. Most of the patients had haematological malignancies (78%). The reason for ICU admission was shock in half of the patients (n = 19, 53%) and respiratory failure in thirteen patients (36%). Median SOFA score was 8.5 IQR [7; 15]. Time between ICU admission and fungal diagnosis was 2.5 days [-1; 4]. Infection was disseminated in 27 (75%) patients with positive blood cultures in 25 patients (69%). Thirty patients (83%) received curative antifungal treatment in the ICU, in a median time of 1 day [0;1] after ICU admission. Twenty-four patients (67%) died in the ICU and hospital mortality rate was 69%. The number and extent of organ failures, as represented by SOFA score, were associated with mortality. CONCLUSIONS: This study demonstrates poor outcome in critically ill patients with Geotrichum-related infections, which encourages a high level of suspicion.