Paradigm Shift of Interventional Strategies and Outcomes for Acute Limb Ischemia Post-Pandemic.

PURPOSE: We performed a large-scale comparison of patients treated for acute limb ischemia (ALI) in the pre-COVID (2017-2019) and COVID (2020-2022) eras to evaluate changes in interventional strategies and compare factors associated with adverse outcomes. We sought to characterize patient outcomes in an evolving ALI treatment algorithm in response to pandemic-associated presentation delays and rapid technological advancements in mechanical thrombectomy (MT). METHODS: Using the TriNetX global research network, we conducted a multicenter query across 80 health care organizations (HCOs) spanning 4 countries for patients treated for ALI. Propensity score matching was performed to account for comorbidities. Risk of adverse outcomes within 30 days was calculated for each era, including re-intervention (RI30), major/minor amputation, and death. Patients were then stratified by initial intervention: open revascularization (OR), MT, or catheter-directed thrombolysis and adjunctive endovascular procedures alone (CDT/EP). Risk of adverse outcomes was compared between treatment groups of the same era. RESULTS: After propensity score matching, the pre-COVID era and COVID era cohorts included 7344 patients each. COVID era patients experienced a statistically significant higher risk of 30-day mortality (RR=1.211, p=0.027). Mechanical thrombectomy interventions were performed more frequently in the COVID era (RR=1.314, p<0.0001). Comparing outcomes between treatment groups, MT patients required RI30 more than OR patients (pre-COVID: RR=2.074, p=0.006; COVID: RR=1.600, p=0.025). Open revascularization patients had higher 30-day mortality (pre-COVID: RR=2.368, p<0.0001; COVID: RR=2.013, p<0.0001) and major amputations (pre-COVID: RR=2.432, p<0.0001; COVID: RR=2.176, p<0.0001) than CDT/EP. Pre-COVID CDT/EP patients were at higher risk for RI30 (RR=1.449, p=0.005) and minor amputations (RR=1.500, p=0.010) than OR. The MT group had higher major amputation rates than CDT/EP (pre-COVID: RR=2.043, p=0.019; COVID: RR=1.914, p=0.007). COVID-era MT patients had greater 30-day mortality (RR=1.706, p=0.031) and RI30 (RR=1.544, p=0.029) than CDT/EP. CONCLUSION: Significant shifts toward an MT-based approach have been observed in the last 3 years. Although MT required more RI30 than OR, there was no associated consequence of mortality and limb salvage. The increased mortality seen among COVID-era patients could be explained by delayed presentation, as well as poorly understood pro-thrombogenic or pro-inflammatory mechanisms related to the first waves of COVID. More research is necessary to determine an optimal treatment algorithm. CLINICAL IMPACT: Comorbid risk factors and severity of ischemia must be carefully considered before selecting an interventional strategy to prevent adverse outcomes and maximize limb salvage. Open revascularization strategies are associated with increased mortality and limb loss compared to less-invasive thrombolytic therapy alone. Mechanical thrombectomy (MT)-based approaches have been increasingly used in the last 3 years. Patients receiving MT are more likely to require reintervention within 30 days.

The RIPK3 Scaffold Regulates Lung Inflammation During Pseudomonas Aeruginosa Pneumonia.

RIPK3 (receptor-interacting protein kinase 3) activity triggers cell death via necroptosis, whereas scaffold function supports protein binding and cytokine production. To determine if RIPK3 kinase or scaffold domains mediate pathology during Pseudomonas aeruginosa infection, control mice and those with deletion or mutation of RIPK3 and associated signaling partners were subjected to Pseudomonas pneumonia and followed for survival or killed for biologic assays. Murine immune cells were studied in vitro for Pseudomonas-induced cytokine production and cell death, and RIPK3 binding interactions were blocked with the viral inhibitor M45. Human tissue effects were assayed by infecting airway epithelial cells with Pseudomonas and measuring cytokine production after siRNA inhibition of RIPK3. Deletion of RIPK3 reduced inflammation and decreased animal mortality after Pseudomonas pneumonia. RIPK3 kinase inactivation did neither. In cell culture, RIPK3 was dispensable for cell killing by Pseudomonas and instead drove cytokine production that required the RIPK3 scaffold domain but not kinase activity. Blocking the RIP homotypic interaction motif (RHIM) with M45 reduced the inflammatory response to infection in vitro. Similarly, siRNA knockdown of RIPK3 decreased infection-triggered inflammation in human airway epithelial cells. Thus, the RIPK3 scaffold drives deleterious pulmonary inflammation and mortality in a relevant clinical model of Pseudomonas pneumonia. This process is distinct from kinase-mediated necroptosis, requiring only the RIPK3 RHIM. Inhibition of RHIM signaling is a potential strategy to reduce lung inflammation during infection.

Sex-Related Disparities in Acute Limb Ischemia Treatment Outcomes.

BACKGROUND: Although a substantial impetus behind disparities research in healthcare exists, those that are sex-related within vascular surgery outcomes are largely unexplored. Consequently, published guidelines lack specificity when it comes to treating male and female patients with vascular disease. Disparities related to patients suffering from chronic limb-threatening ischemia have been broached, although no extensive studies assessing disparities in acute limb ischemia treatment outcomes have come to the forefront. In this study, our aim is to identify and quantify sex-related disparities as they pertain to interventions for acute limb ischemia. METHODS: Using the TriNetX global research network, we conducted a multicenter query across 48 healthcare organizations spanning 5 countries for patients treated for acute limb ischemia. We determined the number of male and female patients that received one of the following interventions: open revascularization, percutaneous mechanical thrombectomy, or catheter-directed thrombolysis and/or adjunctive endovascular procedures. Propensity score matching was performed to account for comorbidities. Risk of adverse outcomes within 30 days was calculated for each sex, including reintervention, major amputation, and death. Risk of adverse outcomes was then compared between treatment groups of the same sex and between sexes. Type-I errors were reduced through utilization of the Holm-Bonferroni method to correct P values. RESULTS: Within our study, we noted several important findings. Females were more likely to receive catheter-directed thrombolysis and/or adjunctive endovascular procedures (P = 0.001) than males. There were no significant differences in the rates of open revascularization or percutaneous mechanical thrombectomy between males and females. Overall, females were more likely to die within 30 days (P < 0.0001) and greater number of males required reintervention within 30 days (P < 0.0001). Analyzing outcomes within individual treatment groups, females undergoing open revascularization or catheter-directed thrombolysis and/or adjunctive endovascular intervention demonstrated a profound increase in mortality within 30 days of intervention (P = 0.0072 and P = 0.0206, respectively), but these differences were not reflected in the percutaneous mechanical thrombectomy group. Limb salvage rates in females were higher than males overall although there were no significant sex differences within any treatment groups specifically. CONCLUSIONS: In conclusion, there was a significantly higher risk of death in females across all treatment groups in the studied timeframe. Limb salvage rates were higher for females in the open revascularization (OR) treatment group, while males were more likely to require a reintervention across all treatment groups. By evaluating these disparities, we can provide greater insight into personalized treatment for patients presenting with acute limb ischemia.

Early- and Late-Onset Bloodstream Infections in the Intensive Care Unit: A Retrospective 5-Year Study of Patients at a University Hospital in China.

BACKGROUND: Limited data are available regarding the current microbiological characteristics of bloodstream infections (BSIs) in intensive care units (ICUs) in China. This retrospective study aimed to determine the epidemiology of early- and late-onset BSIs in our ICU. METHODS: We retrospectively collected data about ICU patients with BSI from 2013 to 2017. The patients were divided into the early- and late-onset BSI groups according to if BSI occurred within or beyond 48 hours after ICU admission. Univariate and multivariate logistic regression analyses were used to assess the risk factors for infection with multidrug resistant organisms (MDROs). RESULTS: Of 5474 ICU admissions, 486 (8.9%) patients with BSIs and with 500 microorganisms were included in this study, 246 (50.6%) of whom had early-onset BSIs. Two hundred and seventy patients were infected with MDROs. The proportion of MDRO infections was significantly higher among patients with late-onset BSIs than among those with early-onset BSIs (57.9% vs. 41.5%, P = .017). The ICU mortality rate was significantly higher in the late-onset BSI group (44.6% vs. 33.8%, P = .014) and early and appropriate antimicrobial treatment significantly improved the survival rate among patients with BSI (P < .001). CONCLUSIONS: MDROs affected more than half of patients with BSI in the ICU. Early appropriate empirical antimicrobial therapy could improve clinical outcome of patients with BSIs.

The microbiome and nutrition in critical illness.

PURPOSE OF REVIEW: The present review aims to describe the relationship between nutrition and the gut microbiome in critical illness. RECENT FINDINGS: Critical illness disrupts not only cells of human origin but also the intestinal microbiome, with a decrease in bacterial diversity and transformation into a pathobiome. Under basal conditions, nutrition profoundly alters microbial composition with significant salutatory effects on human health. In critical illness, enteral nutrition is recommended and has theoretical (but not proven) advantages towards improved inner microbial health and diminution of bacterial translocation. Dietary supplements such as probiotics and fiber have been shown to improve microbial derangements in health. However, their impact on the microbiome in critical illness is unclear and although they may have some beneficial effects on patient-centric outcomes, they do not alter mortality. The precise mechanisms of how nutrition and dietary supplements modulate the gut microbiome remain to be determined. SUMMARY: Nutrition and supplements such as probiotics appear to play a significant role in modulating the microbiome in health, yet the relationship in critical illness is unclear. Further investigation is required to determine the mechanistic determinants of the impact of nutrition on the microbiome in critical illness and the potential clinical implications of this.

Giant 20 × 35 cm brachial artery pseudoaneurysm after fistulogram treated with surgical resection of pseudoaneurysm and patch angioplasty of brachial artery.

Brachial artery pseudoaneurysms are a rare entity, which can occur secondary to infectious, traumatic, or iatrogenic causes. We present a 78-year-old female with end-stage renal disease on hemodialysis via a right brachio-basilic arteriovenous fistula. She had previously undergone numerous fistulograms and endovascular interventions for right upper extremity swelling due to prolonged bleeding following dialysis. After a recent fistulogram she developed recurrent arm swelling. Duplex showed a large hematoma without any evidence of vascular flow. However, intraoperatively, she was noted to have a giant 20 × 35 cm pseudoaneurysm of the brachial artery. Therapeutic options include endovascular stenting, embolization, thrombin injection, ultrasound-guided compression, and surgery. We elected to perform resection of the large pseudoaneurysm and arteriovenous fistula ligation due to the large size. Given her end-stage renal disease status and lacking quality autogenous vein, we were able to perform a patch angioplasty repair of her brachial artery without requiring a bypass.

Endovascular Coil Embolization of an Enlarging Gastroduodenal Artery Aneurysm.

Gastroduodenal artery aneurysms are a rare type of visceral aneurysm that can lead to rupture and death. We present a 75-year-old male with history of hypertension, diabetes, and hyperlipidemia with an incidental finding of a 3.2 × 3.7 cm gastroduodenal aneurysm found on abdominal computed tomography angiography (CTA). After refusing surgical intervention, he was seen two years later and presented with an enlarged gastroduodenal aneurysm, now 5.0 × 5.1 cm, visible on a repeat abdominal CTA. Upon his continued refusal for an open surgery, we elected for endovascular repair of this GDA aneurysm via coil embolization.

MYOSIN LIGHT CHAIN KINASE DELETION WORSENS LUNG PERMEABILITY AND INCREASES MORTALITY IN PNEUMONIA-INDUCED SEPSIS.

ABSTRACT: Increased epithelial permeability in sepsis is mediated via disruptions in tight junctions, which are closely associated with the perijunctional actin-myosin ring. Genetic deletion of myosin light chain kinase (MLCK) reverses sepsis-induced intestinal hyperpermeability and improves survival in a murine model of intra-abdominal sepsis. In an attempt to determine the generalizability of these findings, this study measured the impact of MLCK deletion on survival and potential associated mechanisms following pneumonia-induced sepsis. MLCK -/- and wild-type mice underwent intratracheal injection of Pseudomonas aeruginosa . Unexpectedly, survival was significantly worse in MLCK -/- mice than wild-type mice. This was associated with increased permeability to Evans blue dye in bronchoalveolar lavage fluid but not in tissue homogenate, suggesting increased alveolar epithelial leak. In addition, bacterial burden was increased in bronchoalveolar lavage fluid. Cytokine array using whole-lung homogenate demonstrated increases in multiple proinflammatory and anti-inflammatory cytokines in knockout mice. These local pulmonary changes were associated with systemic inflammation with increased serum levels of IL-6 and IL-10 and a marked increase in bacteremia in MLCK -/- mice. Increased numbers of both bulk and memory CD4 + T cells were identified in the spleens of knockout mice, with increased early and late activation. These results demonstrate that genetic deletion of MLCK unexpectedly increases mortality in pulmonary sepsis, associated with worsened alveolar epithelial leak and both local and systemic inflammation. This suggests that caution is required in targeting MLCK for therapeutic gain in sepsis.

The IL-27 receptor regulates TIGIT on memory CD4+ T cells during sepsis.

Sepsis is a leading cause of morbidity and mortality associated with significant impairment in memory T cells. These changes include the upregulation of co-inhibitory markers, a decrease in functionality, and an increase in apoptosis. Due to recent studies describing IL-27 regulation of TIGIT and PD-1, we assessed whether IL-27 impacts these co-inhibitory molecules in sepsis. Based on these data, we hypothesized that IL-27 was responsible for T cell dysfunction during sepsis. Using the cecal ligation and puncture (CLP) sepsis model, we found that IL-27Rα was associated with the upregulation of TIGIT on memory CD4+ T cells following CLP. However, IL-27 was not associated with sepsis mortality.

TIGIT modulates sepsis-induced immune dysregulation in mice with preexisting malignancy.

TIGIT is a recently identified coinhibitory receptor that is upregulated in the setting of cancer and functionally contributes to the impairment of antitumor immunity. However, its role during sepsis is unknown. Because patients with cancer are 10 times more likely to die of sepsis than previously healthy (PH) patients with sepsis, we interrogated the role of TIGIT during sepsis in the context of preexistent malignancy. PH mice or cancer (CA) mice inoculated with lung carcinoma cells were made septic by cecal ligation and puncture (CLP). We found that sepsis induced TIGIT upregulation predominantly on Tregs and NK cells in both PH and CA mice. Anti-TIGIT Ab improved the 7-d survival of CA septic mice but not PH mice after CLP. Treatment of CA septic animals but not PH septic animals with anti-TIGIT mAb significantly reversed sepsis-induced loss of CD4+ T cells, CD8+ T cells, Foxp3+ Treg, and CD19+ B cells in the spleen, which was the result of decreased caspase-3+ apoptotic cells. In sum, we found that anti-TIGIT Ab reversed sepsis-induced T cell apoptosis in CA septic mice and led to a significant survival benefit, suggesting its use as a potential immunotherapy to improve outcomes in septic patients with cancer.

Preexisting malignancy abrogates the beneficial effects of CXCR4 blockade during sepsis.

Patients with cancer are at an increased risk of developing and dying from sepsis. We previously reported that blockade of the chemokine receptor CXCR4 resulted in decreased CD4+ T cell exhaustion and improved survival in a model of polymicrobial sepsis in previously healthy mice. Here, we sought to determine whether CXCR4 blockade could improve mortality and immune dysregulation during sepsis complicated with malignancy. Results in animals inoculated with a lung cancer cell line and subjected to CLP 3 weeks later indicated that CXCR4 was up-regulated on naïve and central memory T cells following sepsis. Of note, and in contrast to results in previously healthy mice, CXCR4 blockade failed to improve survival in cancer septic animals; instead, it actually significantly worsened survival. In the setting of cancer, CXCR4 blockade failed to result in T cell egress from the bone marrow, reverse lymphopenia in the spleen, or reverse T cell exhaustion. Mechanistically, elevated expression of CD69 on naïve T cells in the bone marrow of cancer septic animals was associated with their inability to egress from the bone marrow in the setting of CXCR4 blockade. In conclusion, these results illuminate the differential impact of CXCR4 blockade on sepsis pathophysiology in the setting of cancer and highlight the need for personalized therapy during sepsis.

Critical illness and the role of the microbiome.

The number of microbes living within the intestinal lumen is similar to the number of all cells of human origin in the host. Although historically little attention has been paid to the massive microbial community residing inside each of us, the last few years have witnessed an explosion of information related to the role of the microbiome in the maintenance of health and in the pathogenesis of disease. Here, we review data suggesting that the microbiome is converted into a pathobiome in critical illness and potential strategies for targeting the microbiome for therapeutic gain in the intensive care unit.

Chronic Alcohol Ingestion Worsens Survival and Alters Gut Epithelial Apoptosis and CD8+ T Cell Function After Pseudomonas Aeruginosa Pneumonia-Induced Sepsis.

Mortality is higher in septic patients with a history of alcohol use disorder than in septic patients without a history of chronic alcohol usage. We have previously described a model of chronic alcohol ingestion followed by sepsis from cecal ligation and puncture in which alcohol-fed septic mice have higher mortality than water-fed septic mice, associated with altered gut integrity and increased production of TNF and IFNγ by splenic CD4 T cells without alterations in CD8 T cell function. The purpose of this study was to determine whether this represents a common host response to the combination of alcohol and sepsis by creating a new model in which mice with chronic alcohol ingestion were subjected to a different model of sepsis. C57Bl/6 mice were randomized to receive either alcohol or water for 12 weeks and then subjected to Pseudomonas aeruginosa pneumonia. Mice were sacrificed either 24 hours after the onset of sepsis or followed for survival. Alcohol-fed septic mice had significantly higher 7-day mortality than water-fed septic mice (96% vs 58%). This was associated with a 5-fold increase in intestinal apoptosis in alcohol-fed septic animals, accompanied by an increase in the pro-apoptotic protein Bax. Serum IL-6 levels were higher and IL-2 levels were lower in alcohol-fed septic mice. In contrast, CD8 T cell frequency was lower in alcohol-fed mice than water-fed septic mice, associated with increased production of IFNγ and TNF in stimulated splenocytes. No significant differences were noted in CD4 T cells, lung injury or bacteremia. Mice with chronic alcohol ingestion thus have increased mortality regardless of their septic insult, associated with changes in both the gut and the immune system.

Murine Pancreatic Cancer Alters T Cell Activation and Apoptosis and Worsens Survival After Cecal Ligation and Puncture.

Patients with cancer who develop sepsis have a markedly higher mortality than patients who were healthy prior to the onset of sepsis. Potential mechanisms underlying this difference have previously been examined in two preclinical models of cancer followed by sepsis. Both pancreatic cancer/pneumonia and lung cancer/cecal ligation and puncture (CLP) increase murine mortality, associated with alterations in lymphocyte apoptosis and intestinal integrity. However, pancreatic cancer/pneumonia decreases lymphocyte apoptosis and increases gut apoptosis while lung cancer/CLP increases lymphocyte apoptosis and decreases intestinal proliferation. These results cannot distinguish the individual roles of cancer versus sepsis since different models of each were used. We therefore created a new cancer/sepsis model to standardize each variable. Mice were injected with a pancreatic cancer cell line and 3 weeks later cancer mice and healthy mice were subjected to CLP. Cancer septic mice had a significantly higher 10-day mortality than previously healthy septic mice. Cancer septic mice had increased CD4 T cells and CD8 T cells, associated with decreased CD4 T cell apoptosis 24 h after CLP. Further, splenic CD8+ T cell activation was decreased in cancer septic mice. In contrast, no differences were noted in intestinal apoptosis, proliferation, or permeability, nor were changes noted in local bacterial burden, renal, liver, or pulmonary injury. Cancer septic mice thus have consistently reduced survival compared with previously healthy septic mice, independent of the cancer or sepsis model utilized. Changes in lymphocyte apoptosis are common to cancer model and independent of sepsis model, whereas gut apoptosis is common to sepsis model and independent of cancer model. The host response to the combination of cancer and sepsis is dependent, at least in part, on both chronic comorbidity and acute illness.

Increased mortality in CD43-deficient mice during sepsis.

CD43 is a large transmembrane protein involved in T cell activation. Previous studies of CD43-/- mice in viral models have demonstrated a role for CD43 in Th1/Th2 skewing, activation of Foxp3+ Treg, and T cell apoptosis. However, the role of CD43 during sepsis has never been tested. Thus, we interrogated the role of CD43 during sepsis using a murine cecal ligation and puncture (CLP) model, and found that CD43-/- mice demonstrated significantly worsened mortality compared to B6 mice following CLP. Phenotypic analysis of splenocytes isolated 24 h after septic insult revealed significantly increased apoptosis of central memory cells in both CD4+ and CD8+ T cell compartments in CD43-/- septic mice compared to WT septic mice. Furthermore, CD43-/-septic mice exhibited a prominent Th2 skewing following sepsis relative to WT septic mice, as evidenced by a significant decrease in the frequency of IL-2+ CXCR3+ TH1 cells as a significant increase in the frequency of IL-4+ CCR4+ TH2 cells. Finally, septic CD43-/- animals contained significantly fewer CD25+ Foxp3+ TReg cells as compared to WT septic animals. Importantly, depleting CD25+ Treg eliminated the increased mortality observed in CD43-/- mice. Taken together, these data demonstrate an important role of CD43 in modulating immune dysregulation and mortality following sepsis.