Septic Shock Syndrome Research Articles

Opportunities and Challenges of Application of Cytosorb Therapy in Sepsis Management

Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection. In 2017, an estimated 48·9 million incident cases of sepsis were recorded worldwide, and 11·0 million sepsis-related deaths were reported, representing 19·7% of all global deaths.1 Though overall data related to sepsis is poor but it is also a major health care challenge for resource limited countries. Severe sepsis is a significant & common health problem in ICU patients of Bangladesh2. A continuum of severity from sepsis to septic shock and multi-organ dysfunction syndrome (MODS) exists. MODS is a clinical syndrome characterized by the development of progressive and potentially reversible physiologic dysfunction in 2 or more organs or organ systems that is induced by a variety of acute insults, including sepsis. Sepsis leads to malignant intravascular inflammation, coagulopathy, circulatory derangement, tissue hypoxia, cytotoxicity and apoptosis. As a result, dysfunction of vital organ systems occur. Host response and other factors influenc outcome. Patients with sepsis must be treated with-timely, appropriate antibiotics, intravenousfluids, vasopressor and inotropic support & oxygen therapy.3 Other additional treatments including extracorporeal blood purification techniques (BPT). These techniques include hemofiltration, hemoperfusion, intermittent or continuous high-volume hemofiltration (HVHF), plasmapheresis or adsorption.4 The rationale behind such an approach is to achieve “immune homeostasis” which theoretically reduces the potential damage caused by dysregulation of the host response to infection. Given the pivotal role of cytokine production in sepsis, it follows that removal of these substances, through such BPT, may attenuate the response particularly in the early phase of sepsis.5 Indications include 1) Rhabdomyolysis resulting from Reperfusion syndrome, Trauma, Malignant Hyperthermia. 2) External injuries including Sepsis/Septic shock, Hemorrhagic shock, Trauma, Ruptured aortic aneurysm, Post-Cardiac Arrest Syndrome, Cardio-pulmonary resuscitation, Extensive surgery, Organ transplantation, Cardiosurgical intervention, Severe skin and soft tissue damage, Burns, Necrotizing fasciitis, Post-Cardiotomy Syndrome, Acute Respiratory Distress Syndrome. 3) Diseases: Pancreatitis, Liver insufficiency, Renal insufficiency, Stroke, Myocardial infarction, Cardiogenic shock/Heart failure, Tumor Lysis Syndrome, Hemophagocytosis Syndrome. Liver failure/Hyperbilirubinemia bridging to transplant or to recovery, Life-threatening bleeding under Direct Oral Anticoagulants (DOAC)6. Bangladesh Crit Care J September 2024; 12 (2): 79-80

Comparison of Outcomes of Bell’s Palsy Patients Treated with Steroid and Steroid with Antiviral Drug in a Tertiary Care Hospital

Background: Bell’s palsy is the most common acute mononeuropathy associated with idiopathic unilateral facial weakness, characterized by facial asymmetry. Though steroids have effectiveness in managing Bell’s palsy, the use of antiviral is still debatable. Objective: To compare the outcome of Bell’s palsy with treatment by steroid versus combination of steroid and antiviral drugs. Methodology: A prospective analytical study was performed on 84 patients with acute Bell’s palsy attending at Neurology outpatient department of Mymensingh Medical College Hospital from July 2014 to June 2016. The patients were divided into two groups purposively after initial assessment as per House-Brackmann grading system (HBS). Group-I patients were treated with oral prednisolone and oral valacyclovir and Group-II patients were treated with oral prednisolone only. Both groups received facial exercises as per demonstration and proper eye care throughout the study period. Follow-up was done after 2 weeks, 4 weeks and 3 months for collection of data about recovery according to reassessment. Results: The analysis revealed that recovery rates at all 3 follow-ups were higher in the combination group than that of the prednisolone-only group [29(67.44%) versus 18 (43.90%) at 2nd week follow-up, 35(81.39%) versus 25(60.97%) at 4th week follow up and 40 (93.02%) versus 30(73.17%) at 3rd month follow-up]. Moreover, the expected recovery rate was higher in severe Bell’s palsy patients in the combination group than in steroid-alone group (22, 88.0% complete recovery versus 13, 54.17% complete recovery at the end of 3 months of treatment) [p=0.034]. haemorrhagic shock, spinal cord damage, septic shock and crush syndrome. Conclusion: The study showed antiviral (valacyclovir) plus steroid (prednisolone) to be more effective than steroid (prednisolone) alone in the treatment of Bell’s palsy. Moreover, outcome was more favorable in combination groups presenting with severe disease. Lessen their severity. Journal of Monno Medical College December, 2023; 9 (2):58-62

Forensic Profiling of Road Traffic Accident Victims- A Retrospective Study

Background: Road traffic accidents (RTAs) have become a significant public health problem that requires a multi-disciplinary strategy to solve. Every year, 1.35 million people die because of RTAs. The effects of a traffic accident not only cause the sufferer to suffer physically, emotionally, and financially, but they also have a deadly impact on the way the entire family functions. Objectives: This study's objective was to assess the current RTA situation in Manikganj district, determine the injury pattern, explore the causes and frequency of accidents, and find out the sociodemographic characteristics of the victims. Methodology: This retrospective study was carried out in the Manikganj District hospital, Bangladesh, during the period of January, 2019 to December, 2020. Results: During the study period, there were 381 postmortems performed, of which 83 (21.78%) instances involved RTA. Of the victims, 49(59.04%) were men and 34(40.96%) women. Incidence of RTA (24, 28.91%) was the highest among people aged 21 to 30 years. The most accidents happened during the daytime (32, 38.55%). All victims sustained many abrasions and bruises (83, 100%), laceration was present in 46(55.42%), fractured ribs in 33(39.75%), fractured hipbones in 32(38.55%), skull bones fractured in 16(19.27%), head injury in 26 (31.32%) and intracranial haemorrhages in 26(31.32%) cases. Most victims (59, 71.08%) were pedestrians, followed by passengers and drivers. In 83 instances, head injuries accounted for most fatalities (22, 26.53%), followed by multiple traumas, haemorrhagic shock, spinal cord damage, septic shock and crush syndrome. Conclusion: Strict adherence to traffic laws, public awareness campaigns, and adequate driver training all reduce the likelihood of road accidents and lessen their severity. Journal of Monno Medical College December, 2023; 9 (2):53-57

Corticosteroids for Managing Pediatric Sepsis and Septic Shock: A Systematic Review and Meta-analysis.

To assess the efficacy and safety of corticosteroids for the management of pediatric sepsis and septic shock. Ovid MEDLINE, Ovid Embase, CENTRAL, Web of Science (Core Collection) and China National Knowledge Infrastructure were systematically searched up to September 2023. Preprint servers, clinical trial registries and the reference sections of previous reviews were hand-searched. Randomized controlled trials that enrolled pediatric sepsis, septic shock or systemic inflammatory response syndrome patients, compared the use of corticosteroid regimens against standard sepsis care and reported eligible outcomes were included. Title/abstract and full-text screening were conducted in-duplicate. Eligible articles were extracted using a standardized form in-duplicate. Outcomes extracted include mortality incidence, hospital and pediatric intensive care unit length of stay, duration of shock, incidence of adverse events and serious adverse events and incidence of corticosteroid-related adverse events. The risk of bias was assessed using the Revised Cochrane Risk of Bias Tool for Assessing Randomized Trials. Random-effects meta-analyses were conducted, and the quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations approach. Sixteen randomized controlled trials (N = 973) were included. Corticosteroid use may be associated with reduced mortality risks (risk ratio: 0.65, 95% CI: 0.50-0.85), shorter length of hospital stay (MD: -3.76 days, 95% CI: -6.66 to -0.86), and shorter pediatric intensive care unit length of stay (MD -2.34 days, 95% CI: -3.14 to -1.53 days). Corticosteroid use may be associated with gastrointestinal bleeding but not a higher risk of secondary infection. No studies reported on serious adverse events. All findings were based on low to very low quality of evidence. While corticosteroids show promise for managing pediatric sepsis and septic shock, the question of how to select the best candidate and the most optimal regimen remains unanswered. Future trials need to focus on assessing corticosteroid-related adverse events and stratifying patient inclusion by sepsis subphenotypes.

Identifying high-risk undifferentiated emergency department patients with hyperlactatemia: Predictors of 30-day in-hospital mortality.

Hyperlactatemia has been recognized as a significant prognostic indicator in critically ill patients. Nonetheless, there remains a gap in understanding the specific risk factors contributing to increased mortality among undifferentiated emergency department (ED) patients presenting with elevated lactate levels. The objective of the study is to investigate potential risk factors for 30-day in-hospital mortality in ED patients with hyperlactatemia. All nontraumatic adult presentations to the ED who had a lactate level of ≥2.5 mmol/L were included. Comorbidities, vital signs, lactate levels, lactate clearance, lactate normalization, and final diagnosis were compared with 30-day in-hospital mortality. A 30-day in-hospital mortality rate of 10.4% was observed in 979 patients. The mortality rate was higher in hypotensive patients (odds ratio [OR] 4.973), in nursing home patients (OR 5.689), and bedridden patients (OR 3.879). The area under the curve for the second lactate level (0.804) was higher than the first lactate level (0.691), and lactate clearance (0.747) for in-hospital mortality. A second lactate level >3.15 mmol/l had a sensitivity of 81.3% in predicting in-hospital mortality. The OR for mortality was 6.679 in patients without lactate normalization. A higher mortality rate was observed in patients with acute renal failure (OR 4.305), septic shock (OR 4.110), and acute coronary syndrome (OR 2.303). A second lactate measurement more accurately predicts in-hospital mortality than lactate clearance and the first lactate level in ED patients. Nursing home patients, bed-ridden patients, hypotensive patients on initial ED presentation, patients without lactate normalization, and patients with a final diagnosis of acute renal failure, septic shock, and acute coronary syndrome had a higher mortality rate.

Potential biomarkers used for risk estimation of pediatric sepsis-associated organ dysfunction and immune dysregulation.

Pediatric sepsis is a serious issue globally and is a significant cause of illness and death among infants and children. Refractory septic shock and multiple organ dysfunction syndrome are the primary causes of mortality in children with sepsis. However, there is incomplete understanding of mechanistic insight of sepsis associated organ dysfunction. Biomarkers present during the body's response to infection-related inflammation can be used for screening, diagnosis, risk stratification/prognostication, and/or guidance in treatment decision-making. Research on biomarkers in children with sepsis can provide information about the risk of poor outcomes and sepsis-related organ dysfunction. This review focuses on clinically used biomarkers associated with immune dysregulation and organ dysfunction in pediatric sepsis, which could be useful for developing precision medicine strategies in pediatric sepsis management in the future. IMPACT: Sepsis is a complex syndrome with diverse clinical presentations, where organ dysfunction is a key factor in morbidity and mortality. Early detection of organ complications is vital in sepsis management, and potential biomarkers offer promise for precision medicine in pediatric cases. Well-designed studies are needed to identify phase-specific biomarkers and improve outcomes through more precise management.

Role of growth arrest-specific protein 6 in diagnosis and prognosis of sepsis in infants and children

Background Sepsis is a main cause of mortality in the pediatrics and neonates. Early goal-directed therapy is the cornerstone in sepsis management that is focuses on keeping organ perfusion and function normally. Diagnosis of pediatric sepsis in the emergency department is considered a significant challenge for clinicians for many reasons. These include a lack of fast and accurate diagnostic tools, an absence of simple and specific diagnostic criteria, and unclear symptoms during the early phase of illness. The best predictive tool in the future will likely be a combination of multiple biomarkers and physiomarkers. Growth arrest-specific protein 6 (Gas6) is an anti-apoptotic vitamin-K-dependent protein. It is secreted by endothelial cells and is important for the activation of endothelium during inflammation. Several studies hypothesize the use of Gas6 as a biomarker in the pathophysiology of sepsis, an early predictor of mortality, and were able to identify some life-threatening sepsis complications. Aim Evaluation of the diagnostic and prognostic values of plasma Gas6 in patients with sepsis, septic shock, and multiple organ dysfunction syndrome in infants and children. Patients and methods Case-control study was carried out from April 2019 to April 2020. 90 children were included and divided into two equal groups (cases and controls). The patients aged from 1 month to 18 years were diagnosed with sepsis, septic shock, or multiple organ dysfunction syndrome in the pediatric intensive care unit of Mansoura University Children’s Hospital. The level of plasma Gas6 was measured in both cases and controls and evaluated as regards its relation to diagnosis and outcome of the cases. Results The two groups were age and sex matched. The outcome of the cases group was: 16 cases are discharged, and 29 died. A significant elevation of plasma Gas6 level in the cases more than the controls (sensitivity= 84.4% and specificity= 66.7%). However, no statistically significant difference as regard the relation between plasma Gas6 level and the outcome of the cases (sensitivity= 55.2% and specificity= 62.7%). Conclusion Gas6 show statistically significant elevation in cases of sepsis, septic shock and multiorgan failure. Gas6 plasma level has high accuracy in prediction of sepsis and can be considered as a good negative marker of sepsis but not a reliable prognostic marker in septic patients.

In-hospital mortality of patients with periprosthetic joint infection.

Periprosthetic joint infection (PJI) demonstrates the most feared complication after total joint replacement (TJR). The current work analyzes the demographic, comorbidity, and complication profiles of all patients who had in-hospital treatment due to PJI. Furthermore, it aims to evaluate the in-hospital mortality of patients with PJI and analyze possible risk factors in terms of secondary diagnosis, diagnostic procedures, and complications. In a retrospective, cross-sectional study design, we gathered all patients with PJI (International Classification of Diseases (ICD)-10 code: T84.5) and resulting in-hospital treatment in Germany between 1 January 2019 and 31 December 2022. Data were provided by the Institute for the Hospital Remuneration System in Germany. Demographic data, in-hospital deaths, need for intensive care therapy, secondary diagnosis, complications, and use of diagnostic instruments were assessed. Odds ratios (ORs) with 95% confidence intervals (CIs) for in-hospital mortality were calculated. A total of 52,286 patients were included, of whom 1,804 (3.5%) died. Hypertension, diabetes mellitus, and obesity, the most frequent comorbidities, were not associated with higher in-hospital mortality. Cardiac diseases as atrial fibrillation, cardiac pacemaker, or three-vessel coronary heart disease showed the highest risk for in-hospital mortality. Postoperative anaemia occurred in two-thirds of patients and showed an increased in-hospital mortality (OR 1.72; p < 0.001). Severe complications, such as organ failure, systemic inflammatory response syndrome (SIRS), or septic shock syndrome showed by far the highest association with in-hospital mortality (OR 39.20; 95% CI 33.07 to 46.46; p < 0.001). These findings highlight the menace coming from PJI. It can culminate in multi-organ failure, SIRS, or septic shock syndrome, along with very high rates of in-hospital mortality, thereby highlighting the vulnerability of these patients. Particular attention should be paid to patients with cardiac comorbidities such as atrial fibrillation or three-vessel coronary heart disease. Risk factors should be optimized preoperatively, anticoagulant therapy stopped and restarted on time, and sufficient patient blood management should be emphasized.

A tagging polymorphism in fat mass and obesity-associated (FTO) gene is associated with sepsis status in children.

Sepsis is one of the most common causes of death in patients admitted to intensive care units (ICUs). The development of sepsis is significantly influenced by genetic predisposition. In this study, we highlight a potential association between a variant of the fat mass and obesity-associated (FTO) gene and risk of sepsis in children and adolescents. We investigated a first-intron tagging FTO polymorphism (rs17817449) by comparing a severe condition (SC) group, comprising 598 paediatric patients (ages 0-19 years) admitted to an ICU with fever, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, or multiple organ dysfunction syndrome (MODS), with a control group consisting of 616 healthy young adults. We observed a lower prevalence (p < 0.01; OR = 0.59, 95% CI = 0.39-0.87) of the FTO TT genotype in febrile and SIRS patients compared to patients with severe illness. There was a borderline trend towards a lower prevalence of the FTO TT genotype in the control group compared to the SC group (p < 0.09, OR = 0.81, 95% CI = 0.62-1.06). Our findings suggest that rs17817449, a common FTO polymorphism, may be a predictor of sepsis in paediatric patients, and that higher body weight is protective against this clinical complication.

Clinical features and genetic analysis of three patients with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome due to variants of FOXP3 gene

To analyze the clinical characteristics of three patients with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Three patients with IPEX syndrome diagnosed at the Children's Hospital of Fudan University from January 24, 2013 to July 29, 2019 were selected as the study subjects. Their clinical features, laboratory investigations and results of genetic testing were summarized. Treatment and prognosis were also explored. All of the three children had developed the disorder during infancy. One child had initial features including diabetes and diabetic ketoacidosis, whilst the other two had initiated by diarrhea. All patients had gastrointestinal involvement, and one was diagnosed as very early onset inflammatory bowel disease by colonoscopy and biopsy. Two children also had endocrine glands involvement. One child had manifested type 1 diabetes and positivity for thyroglobulin and thyroid peroxidase antibodies, though his thyroid function had remained normal. Another one had hypothyroidism and was treated by levothyroxine. Genetic testing revealed that all children had harbored missense variants of the FOXP3 gene, including c.1222G>A (p.V408M), c.767T>C (p.M256T) and c.1021A>G (p.T341A). The clinical symptoms of one patient were alleviated following allogeneic hematopoietic stem cell transplantation. One patient was stable after treatment with infliximab plus insulin, and one child had died of refractory septic shock and multiple organ dysfunction syndrome at 3 months old. FOXP3 gene variant-associated IPEX syndrome may have very early onset and diverse clinical manifestations. For male patients with infantile onset chronic diarrhea, multiple endocrine or multiple system involvement, genetic testing is recommended, which may facilitate early diagnosis, treatment and genetic counseling.

Alleviation of Post-sepsis Ischaemia by Drag-Reducing Polymers.

Sepsis, leading to septic shock and multiple organ dysfunction syndrome, is characterised by inflammation, coagulopathy, and microvascular dysfunction, the primary cause of in-hospital mortality. Novel approaches are needed to prevent the consequences of sepsis. We showed that nanomolar concentrations of intravascular blood-soluble drag-reducing polymers (DRPs) significantly improve microvascular perfusion and tissue oxygenation and protect neurons in rat brains after traumatic brain injury and haemorrhagic shock. The aim of this work was to determine whether DRPs-enhanced perfusion could alleviate sepsis-associated microvascular dysregulation in a mouse model of lipopolysaccharide (LPS)-induced sepsis. LPS (Salmonella Thyphosa, 10mg/kg, i.v.) was administered intravenously to induce acute sepsis in C57BL/6 J mice. DRPs (final concentration 5ppm in the blood) or saline was injected i.v. (10 mice/group) 1h after LPS injection to evaluate the efficacy of haemorheological modulation of microvascular dysregulation. In-vivo two-photon laser scanning microscopy was used to monitor cerebral (parietal cortex) and peripheral (ear) microcirculation (i.v. fluorescein isothiocyanate dextran) and tissue oxygen supply (nicotinamide adenine dinucleotide autofluorescence) at a baseline and during 4h after septic shock induction. Differences between groups were determined using a two-way analysis of variance for multiple comparisons with post hoc testing. The statistical significance was set at p<0.05. LPS-induced sepsis led to microvascular dysfunction and tissue hypoxia in the brain and peripheral tissue (ear). DRPs alleviated microthrombosis formation, microvascular dysfunction, and tissue hypoxia in the brain and peripheral tissue compared to the saline control group (p<0.05). Therefore, haemorheological modulation of blood flow by DRPs effectively improves systemic and peripheral circulation, reducing microthrombosis formation, microvascular dysfunction, and tissue hypoxia that can alleviate sepsis, shock, and multiple organ dysfunction syndrome.

Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units.

Intensive care units (ICUs) are expert hospital areas that provide treatment and 24 h care for people who are very sick. Sepsis represents a serious, severe condition and it can lead to septic shock and multiple organ dysfunction syndromes and is one of the most common reasons for patients' hospitalization in ICUs. We wanted to explore the prognostic values of interleukin (IL) 33, soluble suppression of tumorigenicity 2 (sST2), IL 27, and galectin 3 in critically-ill patients. We assumed that these parameters in combination or alone could predict mortality in ICU patients. This research represents a clinical non-randomized prospective study, performed at the Medical Military Academy, a tertiary care hospital in Belgrade, Serbia. The patients were divided in four groups: patients with sepsis (peritonitis, pancreatitis, trauma) and patients without sepsis (trauma). Total number of patients enrolled in the study was 151 and average years of patients were 56.48. The values greater than the cut-off were the predictors of mortality. The IL-33, IL-27 as well as galectin-3 can successfully predict the outcome of critically-ill patients in ICUs. The sST2, cannot predict death in critically-ill patients as a single prognostic factor. However, the combination of at least two biomarkers: IL-33, sST2, IL-27, and galectin-3, gives very significant results in predicting the outcome in patients admitted to ICUs.

The efficacy of Omega-3 polyunsaturated fatty acids for severe burn patients: A systematic review and trial sequential meta-analysis of randomized controlled trials

Severe burns lead to metabolic changes, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. Omege-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties. In the absence of substantial evidence for use on major burns, we systematically reviewed the efficacy of omega-3 PUFAs for patients with severe burns. We comprehensively searched MEDLINE, Web of Science, Embase, Cochrane Library, China National Knowledge Internet, Wang Fang Data, Chinese Biomedicine Database, and Science Direct databases to collect randomised controlled trials of omega-3 PUFAs administered to patients with burns from January 2000 to June 2023. Two researchers independently screened the literatures, extracted the data, and assessed the risk of bias in the included studies. The outcomes were mortality, the risk of severe sepsis, septic shock, and multiple organ dysfunction syndrome. Data synthesis was conducted using Review Manager. Trial sequential analyses (TSA) for outcomes were performed. Three randomised controlled trials involving 140 patients were included. Of these, 71 patients received omega-3 PUFAs. The results showed that omega-3 PUFAs significantly reduced the incidence of severe sepsis, septic shock, multiple organ dysfunction syndrome (RR=0.38, 95% CI [0.19, 0.75], P=0.005), C-reactive protein levels (MD=-39.70[-81.63, 2.23], P=0.06), and improved respiratory outcomes. However, there was no difference in 14-day mortality (RR=1.10, 95%CI [0.59, 2.05], P=0.75). TSA showed that the results for the incidence of severe sepsis, septic shock, multiple organ dysfunction syndrome are insufficient and inconclusive. Omega-3 PUFAs may reduce inflammatory response and risk of sepsis, septic shock, and multiple organ dysfunction syndrome in severe burns patients and may shorten hospital stay but cannot reduce risk of death. Due to the limitation of the quantity and quality of the included studies, the evidence level is low, and the conclusions need to be verified by larger scale and higher quality randomised controlled trials.

Traumatic degloving injuries: a prospective study to assess injury patterns, management, and outcomes at a single center in northern India.

This study investigated the epidemiology, management, outcomes, and postoperative disabilities of degloving soft tissue injuries (DSTIs) treated at a tertiary care center in northern India. A prospective study of patients with DSTIs was conducted over 15 months. The type of degloving injury, the mechanism of injury, and any associated injuries were analyzed using the World Health Organization Disability Assessment Schedule (WHODAS) 2.0 along with the management, outcomes, and disabilities at a 3-month follow-up. Among 75 patients with DSTIs, the average age was 27.5 years, 80.0% were male, and 76.0% had been injured in traffic accidents. The majority (93.3%) were open degloving injuries. Lower limbs were affected most often (62.7%), followed by upper limbs (32.0%). Fractures were the most commonly associated injuries (72.0%). Most patients required more than two procedures, including secondary debridement (41.3%), split skin grafting (80.0%), flap coverage (12.0%), or vacuum-assisted closure (24.0%), while five patients underwent conservative management for closed degloving injuries. Postoperative complications included surgical site infections (14.7%) and skin necrosis (10.7%). Two patients died due to septic shock and multiple organ dysfunction syndrome. The mean length of hospital stay was 11.5±8.1 days, with injuries affecting the lower limbs and perineum requiring longer hospital stays. The mean WHODAS 2.0 disability score at 3 months was 19. Most patients had mild disabilities. Time away from work depended largely upon the site and severity of the injury. Approximately 75% of patients resumed their previous job or study, 14% changed their job, and 8% stopped working completely due to residual disability. DSTIs are common injuries in trauma and management is challenging. Although open DSTI are clinically evident at secondary survey, closed degloving injuries may be missed in the primary survey, necessitating a high index of suspicion, thorough clinical examination, and protocol-based management. Primary preventive strategies (e.g., road safety protocols, preplacement training, and proper protective equipment in industries) are also needed to reduce the incidence of these injuries.

Non-Canonical Inflammasome Pathway: The Role of Cell Death and Inflammation in Ehrlichiosis.

Activating inflammatory caspases and releasing pro-inflammatory mediators are two essential functions of inflammasomes which are triggered in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). The canonical inflammasome pathway involves the activation of inflammasome and its downstream pathway via the adaptor ASC protein, which causes caspase 1 activation and, eventually, the cleavage of pro-IL-1b and pro-IL-18. The non-canonical inflammasome pathway is induced upon detecting cytosolic lipopolysaccharide (LPS) by NLRP3 inflammasome in Gram-negative bacteria. The activation of NLRP3 triggers the cleavage of murine caspase 11 (human caspase 4 or caspase 5), which results in the formation of pores (via gasdermin) to cause pyroptosis. Ehrlichia is an obligately intracellular bacterium which is responsible for causing human monocytic ehrlichiosis (HME), a potentially lethal disease similar to toxic shock syndrome and septic shock syndrome. Several studies have indicated that canonical and non-canonical inflammasome activation is a crucial pathogenic mechanism that induces dysregulated inflammation and host cellular death in the pathophysiology of HME. Mechanistically, the activation of canonical and non-canonical inflammasome pathways affected by virulent Ehrlichia infection is due to a block in autophagy. This review aims to explore the significance of non-canonical inflammasomes in ehrlichiosis, and how the pathways involving caspases (with the exception of caspase 1) contribute to the pathophysiology of severe and fatal ehrlichiosis. Improving our understanding of the non-canonical inflammatory pathway that cause cell death and inflammation in ehrlichiosis will help the advancement of innovative therapeutic, preventative, and diagnostic approaches to the treatment of ehrlichiosis.

ARI0002h (Cesnicabtagene Autoleucel), an Academic Point-of-Care B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor (CAR) T-Cell Strategy: Activity and Safety after Fractionated Initial Therapy and Booster Dose in 60 Patients with Relapsed/Refractory Multiple Myeloma

Background: We reported the safety and activity ofARI0002h, an academic autologous 4-1BB-based CAR T-cell product with a humanized scFv targeting BCMA in a pilot multicenter clinical trial (CARTBCMA-HCB-01) in 30 patients (pts) with relapsed/refractory multiple myeloma (RRMM) (NCT04309981) (Oliver-Caldés, Lancet Onc 2023). Here, we report results of 30 additional pts (cohort 2) and a longer follow-up of cohort 1. Methods: Pts aged 18-75 years old with RRMM were eligible if they had measurable disease, received ≥2 prior regimens, including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 antibody, and were refractory to the last line of treatment. Bridging therapy was allowed after apheresis. Lymphodepletion (LD) with cyclophosphamide and fludarabine was used. The target dose (3x10 6/kg CAR+cells) was administered in a fractionated manner (10%/30%/60%), with at least 24h between infusions. A second dose of up to 3x10 6 CAR+ cells/kg was planned at least 3 months after the first dose in pts with any kind of response and no limiting side effects; LD was repeated according to CAR-T cell persistence. Primary endpoints were overall response rate (ORR) within the first 3 months and rate of cytokine release syndrome (CRS) and/or neurotoxicity in the first 30 days. Response was assessed as per IMWG criteria and bone marrow minimal residual disease (MRD) was analyzed by next-generation flow at a sensitivity of 10 -6. CART persistence in the peripheral blood (PB) was measured by PCR. Adverse events were graded using CTCAE v5.0. CRS and neurotoxicity were graded according to the American Society for Transplantation and Cellular Therapy criteria. Results: As of March 17 th 2023, 72 pts with RRMM were screened, 69 underwent apheresis and 61 received LD, with 60 pts finally receiving ARI0002h (modified intention-to-treat population). The main features are described in Table 1. 48% required bridging therapy. Median CAR-T cell production and turnaround times were 9 days (IQR 8-10) and 32 (IQR 27-36.5), respectively. Median vein-to-vein time was 41 days (IQR 34-51), with differences between pts receiving or not bridging therapy (48 vs. 36 days; p=0.004). The ORR in the first 3 months was 95% (≥ very good partial response (VGPR) in 77%). Median time to first response was one month. Responses deepened over time, achieving 58% complete response (CR) (55% stringent CR), 30% VGPR, 7% partial response, 1 patient (2%) was refractory and 2 pts (3%) died prior to first evaluation (septic shock and macrophage activation syndrome (MAS)). MRD-negative rates on evaluable samples on days 28 and 100 were 98% and 96%, respectively. With a median follow-up of 23.1 months (95%CI 9.2-37.1), estimated median progression-free survival (PFS) was 15.8 months (CI95% 11.5-22.4) (Figure 1). No differences in PFS were found based on high-risk cytogenetics, plasmacytomas or triple-refractoriness. Median overall survival (OS) was not reached with OS rates at 12 and 18 months of 81% and 69%. Eighteen of 60 (30%) pts died due to disease progression (n=13), COVID19 (n=2), cranial trauma, septic shock and MAS (n=1 each). CRS was observed in 90% with 5% grades ≥ 3. Median time to CRS was 7 days (1-14); median duration of 4.5 days. Mild ICANS was reported in only 2 pts (3%) with no late neurologic events. 6 pts (10%) developed a MAS (4 grades 1-2, 1 grade 3, 1 grade 5). Tocilizumab and steroids were administered in 68% (mainly for persistent grade 1 CRS) and 30% of pts, respectively. 44 out of 55 eligible pts (80%) had already received the booster dose, with no relevant toxicities. Median time after first infusion was 4.4 months; 34% received a second LD. Response was evaluable in 42 pts; 45% (n=19) were already in sCR, 29% (n=12) maintained the response and 26% (n=11) improved the response. Median ARI0002h persistence in PB was 5 months (95%CI 3.0-7.0), with an expansion peak on days 14 (70%) and 28 (19%). At 3 and 6 months, 65% and 52% had measurable CART in peripheral blood, respectively, and 33% of relapsed pts had detectable CART. Increased expression of surface markers associated with exhaustion (PD1 and TIGIT) was observed in CAR+ cells between the time of the final product and day 28 (p&amp;lt;0.001). Conclusion: Results from 30 additional pts and a longer follow-up of the first cohort confirm the deep and durable responses obtained with ARI0002h. The booster dose may be partially responsible for the improvement of responses over time and exhaustion may play a role in relapse.

Efficacy of therapeutic plasma exchange in pediatric cases of acute liver failure as an extracorporeal liver support system

BackgroundAcute liver failure in the pediatric population is often accompanied by deranged metabolism, severe encephalopathy and coagulopathy. A liver transplant is the most viable option for the management of such patients. Therapeutic plasma exchange (TPE) is helpful in improving the liver biochemistry profile, thereby, increasing their likelihood of undergoing a liver transplant MethodThe study was conducted over a period of 3 years (January 2018 to December 2021). Indications mainly consisted of ALF with hepatic encephalopathy, worsening liver parameters in spite of medical management, and candidacy for undergoing a liver transplant. Plasma exchange was performed daily or alternatively until the patient recovered, succumbed, or was stable enough to undergo a transplant. Biochemical parameters serum bilirubin, ALT, AST serum ammonia serum urea, serum creatinine were recorded before and after TPE sessions. ResultsThe study group comprised 14 patients of which a total of 28 TPE was performed. There were a total of 5 cases of cryptogenic ALF, 4 of Wilson disease, 2 cases each of infection-related ALF and autoimmune hepatitis, and a single case of drug-induced hepatitis. A total of 5 out of 14 patients underwent a liver transplant and amongst the 9 who did not undergo a transplant, 4 patients expired due to septic shock syndrome; the remaining 5 were discharged in a stable condition following TPE sessions. The disease-free survival was 78.9% and the transplant-free survival was 35.71%. ConclusionTPE plays a crucial role in improving the biochemistry profile of the liver in children with liver failure.

Prognostic models for estimating severity of disease and predicting 30-day mortality of Hypervirulent Klebsiella pneumoniae infections: a bicentric retrospective study.

Hypervirulent Klebsiella pneumoniae (hvKP) is emerging globally and can cause various, severe infections in healthy individuals. However, the clinical manifestations of hvKP infections are nonspecific, and there is no gold standard for differentiating hvKP strains. Our objective was to develop prognostic models for estimating severity of disease and predicting 30-day all-cause mortality in patients with hvKP infections. We enrolled 116 patients diagnosed with hvKP infections and obtained their demographic and clinical data. Taking septic shock and acute respiratory distress syndrome (ARDS) as the primary outcomes for disease severity and 30-day all-cause mortality as the primary outcome for clinical prognosis, we explored the influencing factors and constructed prognostic models. The results showed that increased Acute Physiologic and Chronic Health Evaluation (APACHE) II score [odds ratio (OR) = 1.146; 95% confidence interval (CI), 1.059-1.240], decreased albumin (ALB) level (OR = 0.867; 95% CI, 0.758-0.990), diabetes (OR = 9.591; 95% CI, 1.766-52.075) and high procalcitonin (PCT) level (OR = 1.051; 95%CI, 1.005-1.099) were independent risk factors for septic shock. And increased APACHE II score (OR = 1.254; 95% CI, 1.110-1.147), community-acquired pneumonia (CAP) (OR = 11.880; 95% CI, 2.524-55.923), and extrahepatic lesion involved (OR = 14.718; 95% CI, 1.005-215.502) were independent risk factors for ARDS. Prognostic models were constructed for disease severity with these independent risk factors, and the models were significantly correlated with continuous renal replacement therapy (CRRT) duration, vasopressor duration, mechanical ventilator duration and length of ICU stay. The 30-day all-cause mortality rate in our study was 28.4%. Younger age [hazard ratio (HR) = 0.947; 95% CI, 0.923-0.973)], increased APACHE II score (HR = 1.157; 95% CI, 1.110-1.207), and decreased ALB level (HR = 0.924; 95% CI, 0.869-0.983) were the independent risk factors for 30-day all-cause mortality. A prediction model for 30-day mortality was constructed, which had a good validation effect. We developed validated models containing routine clinical parameters for estimating disease severity and predicting 30-day mortality in patients with hvKP infections and confirmed their calibration. The models may assist clinicians in assessing disease severity and estimating the 30-day mortality early.

Towards prevention of septic shock syndrome: structural and functional studies of PGRP and its complexes with various PAMPs

Towards prevention of septic shock syndrome: structural and functional studies of PGRP and its complexes with various PAMPs

The Immunoadsorption Effect of Veno-arterial Extracorporeal Membrane Oxygenation in Refractory Septic Shock, Ventilator-associated Pneumonia, and Acute Respiratory Distress Syndrome Following Severe Pulmonary Contusions

Background: The utilization of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for immunoadsorption has proven efficacious in reducing mortality rates among neonatal and pediatric patients afflicted with severe sepsis and septic shock. However, the effectiveness of this treatment in adult patients with septic shock remains controversial. Objective: This study was designed to assess the potential of VA-ECMO as an immunoadsorption therapy in patients with severe sepsis and septic shock. The primary objective of this study is to evaluate the efficacy of VA-ECMO in improving clinical outcomes, including acute respiratory distress syndrome (ARDS) and ventilator-associated pneumonia (VAP), weaning from mechanical ventilation, the length of intensive care unit (ICU) stay, and mortality rates in patients with concurrent severe pulmonary contusions, septic shock, and respiratory failure resulting from ARDS and VAP. Methods: This study enrolled a cohort of 100 adult patients with severe pulmonary contusions resulting in persistent respiratory failure despite ten days of mechanical ventilation. These patients subsequently developed severe sepsis, VAP with ARDS presentation, and high Murray score (&gt;3 points), Sequential Organ Failure Assessment (SOFA) score (&gt; 12 points), and Clinical Pulmonary Infection Score (CPIS) (&gt; 6 points). The patients were then divided into two groups: group A (n = 50) received conventional management, while group B (n = 50) underwent VA-ECMO. Moreover, the outcomes, including improvement in ARDS and VAP, successful weaning from mechanical ventilation, length of ICU stay, improvement of one or all parameters of Murray, SOFA, and CPIS scores, morbidity rate, and mortality rate were compared between the two groups and recorded after 14 days of treatment. Results: This study revealed that patients in group B showed significant improvement in Murray, SOFA, and CPIS scores. Furthermore, a large percentage of patients in group B were successfully weaned from both inotropic support and mechanical ventilation and were discharged from ICU. However, no significant difference in the mortality rate was observed between the two groups. Conclusion: VA-ECMO notably impedes the progression of sepsis, shortens ICU stay, and expedites the weaning from inotropic support and mechanical ventilation. However, it has no impact on the mortality rate of adult patients with septic shock.