Prediction of Readmission Following Sepsis Using Social Determinants of Health.

OBJECTIVES: To determine the predictive value of social determinants of health (SDoH) variables on 30-day readmission following a sepsis hospitalization as compared with traditional clinical variables. DESIGN: Multicenter retrospective cohort study using patient-level data, including demographic, clinical, and survey data. SETTINGS: Thirty-five hospitals across the United States from 2017 to 2021. PATIENTS: Two hundred seventy-one thousand four hundred twenty-eight individuals in the AllofUs initiative, of which 8909 had an index sepsis hospitalization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Unplanned 30-day readmission to the hospital. Multinomial logistic regression models were constructed to account for survival in determination of variables associate with 30-day readmission and are presented as adjusted odds rations (aORs). Of the 8909 sepsis patients in our cohort, 21% had an unplanned hospital readmission within 30 days. Median age (interquartile range) was 54 years (41-65 yr), 4762 (53.4%) were female, and there were self-reported 1612 (18.09%) Black, 2271 (25.49%) Hispanic, and 4642 (52.1%) White individuals. In multinomial logistic regression models accounting for survival, we identified that change to nonphysician provider type due to economic reasons (aOR, 2.55 [2.35-2.74]), delay of receiving medical care due to lack of transportation (aOR, 1.68 [1.62-1.74]), and inability to afford flow-up care (aOR, 1.59 [1.52-1.66]) were strongly and independently associated with a 30-day readmission when adjusting for survival. Patients who lived in a ZIP code with a high percentage of patients in poverty and without health insurance were also more likely to be readmitted within 30 days (aOR, 1.26 [1.22-1.29] and aOR, 1.28 [1.26-1.29], respectively). Finally, we found that having a primary care provider and health insurance were associated with low odds of an unplanned 30-day readmission. CONCLUSIONS: In this multicenter retrospective cohort, several SDoH variables were strongly associated with unplanned 30-day readmission. Models predicting readmission following sepsis hospitalization may benefit from the addition of SDoH factors to traditional clinical variables.

Neutrophil Extracellular Traps (NETs): An Emerging Therapeutic Target to Improve Infectious Diseases Outcomes.

Neutrophils possess a diverse repertoire of pathogen clearance mechanisms, one of which is the formation of neutrophil extracellular traps (NETs). NETs are complexes of histone proteins and DNA coated with proteolytic enzymes that are released extracellularly to entrap pathogens and aid in their clearance, in a process known as NETosis. Intravascular NETosis may drive a massive inflammatory response that has been shown to contribute to morbidity and mortality in many infectious diseases, including malaria, dengue fever, influenza, bacterial sepsis, and SARS-CoV-2 infection. In this review we seek to: (1) summarize the current understanding of NETs; (2) discuss infectious diseases in which NET formation contributes to morbidity and mortality; and (3) explore potential adjunctive therapeutics that may be considered for future study in treating severe infections driven by NET pathophysiology. This includes drugs specifically targeting NET inhibition and FDA-approved drugs that may be repurposed as NET inhibitors.

Immunization with lytic polysaccharide monooxygenase CbpD induces protective immunity against Pseudomonas aeruginosa pneumonia.

Pseudomonas aeruginosa (PA) CbpD belongs to the lytic polysaccharide monooxygenases (LPMOs), a family of enzymes that cleave chitin or related polysaccharides. Here, we demonstrate a virulence role of CbpD in PA pneumonia linked to impairment of host complement function and opsonophagocytic clearance. Following intratracheal challenge, a PA ΔCbpD mutant was more easily cleared and produced less mortality than the wild-type parent strain. The x-ray crystal structure of the CbpD LPMO domain was solved to subatomic resolution (0.75Å) and its two additional domains modeled by small-angle X-ray scattering and Alphafold2 machine-learning algorithms, allowing structure-based immune epitope mapping. Immunization of naive mice with recombinant CbpD generated high IgG antibody titers that promoted human neutrophil opsonophagocytic killing, neutralized enzymatic activity, and protected against lethal PA pneumonia and sepsis. IgG antibodies generated against full-length CbpD or its noncatalytic M2+CBM73 domains were opsonic and protective, even in previously PA-exposed mice, while antibodies targeting the AA10 domain were not. Preexisting antibodies in PA-colonized cystic fibrosis patients primarily target the CbpD AA10 catalytic domain. Further exploration of LPMO family proteins, present across many clinically important and antibiotic-resistant human pathogens, may yield novel and effective vaccine antigens.

Very Low Driving-Pressure Ventilation in Patients With COVID-19 Acute Respiratory Distress Syndrome on Extracorporeal Membrane Oxygenation: A Physiologic Study.

OBJECTIVES: To determine in patients with acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) whether reducing driving pressure (ΔP) would decrease plasma biomarkers of inflammation and lung injury (interleukin-6 [IL-6], IL-8, and the soluble receptor for advanced glycation end-products sRAGE). DESIGN: A single-center prospective physiologic study. SETTING: At a single university medical center. PARTICIPANTS: Adult patients with severe COVID-19 ARDS on VV ECMO. INTERVENTIONS: Participants on VV ECMO had the following biomarkers measured: (1) pre-ECMO with low-tidal-volume ventilation (LTVV), (2) post-ECMO with LTVV, (3) during low-driving-pressure ventilation (LDPV), (4) after 2 hours of very low driving-pressure ventilation (V-LDPV, main intervention ΔP = 1 cmH2O), and (5) 2 hours after returning to LDPV. MAIN MEASUREMENTS AND RESULTS: Twenty-six participants were enrolled; 21 underwent V-LDPV. There was no significant change in IL-6, IL-8, and sRAGE from LDPV to V-LDPV and from V-LDPV to LDPV. Only participants (9 of 21) with nonspontaneous breaths had significant change (p < 0.001) in their tidal volumes (Vt) (mean ± SD), 1.9 ± 0.5, 0.1 ± 0.2, and 2.0 ± 0.7 mL/kg predicted body weight (PBW). Participants with spontaneous breathing, Vt were unchanged-4.5 ± 3.1, 4.7 ± 3.1, and 5.6 ± 2.9 mL/kg PBW (p = 0.481 and p = 0.065, respectively). There was no relationship found when accounting for Vt changes and biomarkers. CONCLUSIONS: Biomarkers did not significantly change with decreased ΔPs or Vt changes during the first 24 hours post-ECMO. Despite deep sedation, reductions in Vt during V-LDPV were not reliably achieved due to spontaneous breaths. Thus, patients on VV ECMO for ARDS may have higher Vt (ie, transpulmonary pressure) than desired despite low ΔPs or Vt.

Abrogation of neutrophil inflammatory pathways and potential reduction of neutrophil-related factors in COVID-19 by intravenous immunoglobulin.

Pathogenesis of lung injury in COVID-19 is not completely understood, leaving gaps in understanding how current treatments modulate the course of COVID-19. Neutrophil numbers and activation state in circulation have been found to correlate with COVID-19 severity, and neutrophil extracellular traps (NETs) have been found in the lung parenchyma of patients with acute respiratory distress syndrome (ARDS) in COVID-19. Targeting the pro-inflammatory functions of neutrophils may diminish lung injury in COVID-19 and ARDS. Neutrophils were isolated from peripheral blood of healthy donors, treated ex vivo with dexamethasone, tocilizumab and intravenous immunoglobulin (IVIG) and NET formation, oxidative burst, and phagocytosis were assessed. Plasma from critically ill COVID-19 patients before and after clinical treatment with IVIG and from healthy donors was assessed for neutrophil activation-related proteins. While dexamethasone and tocilizumab did not affect PMA- and nigericin-induced NET production ex vivo, IVIG induced a dose-dependent abrogation of NET production in both activation models. IVIG also reduced PMA-elicited reactive oxygen species production, but did not alter phagocytosis. COVID-19 patients were found to have elevated levels of cell-free DNA, neutrophil elastase and IL-8 as compared to healthy controls. Levels of both cell-free DNA and neutrophil elastase were lower 5 days after 4 days of daily treatment with IVIG. The lack of impact of dexamethasone or tocilizumab on these neutrophil functions suggests that these therapeutic agents may not act through suppression of neutrophil functions, indicating that the door might still be open for the addition of a neutrophil modulator to the COVID-19 therapeutic repertoire.

Inclusion of social determinants of health improves sepsis readmission prediction models.

OBJECTIVE: Sepsis has a high rate of 30-day unplanned readmissions. Predictive modeling has been suggested as a tool to identify high-risk patients. However, existing sepsis readmission models have low predictive value and most predictive factors in such models are not actionable. MATERIALS AND METHODS: Data from patients enrolled in the AllofUs Research Program cohort from 35 hospitals were used to develop a multicenter validated sepsis-related unplanned readmission model that incorporates clinical and social determinants of health (SDH) to predict 30-day unplanned readmissions. Sepsis cases were identified using concepts represented in the Observational Medical Outcomes Partnership. The dataset included over 60 clinical/laboratory features and over 100 SDH features. RESULTS: Incorporation of SDH factors into our model of clinical and demographic features improves model area under the receiver operating characteristic curve (AUC) significantly (from 0.75 to 0.80; P < .001). Model-agnostic interpretability techniques revealed demographics, economic stability, and delay in getting medical care as important SDH predictive features of unplanned hospital readmissions. DISCUSSION: This work represents one of the largest studies of sepsis readmissions using objective clinical data to date (8935 septic index encounters). SDH are important to determine which sepsis patients are more likely to have an unplanned 30-day readmission. The AllofUS dataset provides granular data from a diverse set of individuals, making this model potentially more generalizable than prior models. CONCLUSION: Use of SDH improves predictive performance of a model to identify which sepsis patients are at high risk of an unplanned 30-day readmission.

Increased Peripheral Blood Neutrophil Activation Phenotypes and Neutrophil Extracellular Trap Formation in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients: A Case Series and Review of the Literature.

BACKGROUND: Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets. METHODS: Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English. RESULTS: Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1ß, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P < .0001). COVID-19 neutrophils had exaggerated oxidative burst (P < .0001), NETosis (P < .0001), and phagocytosis (P < .0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected lungs available for examination (2 of 5). While elevations in IL-8 and absolute neutrophil count correlated with disease severity, plasma IL-8 levels alone correlated with death. CONCLUSIONS: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.

A unique case of Miller Fisher-Guillain-Barré overlap syndrome in a liver transplant recipient.

Guillain-Barré syndrome (GBS) is an ascending demyelinating polyneuropathy often associated with recent infection. Miller Fisher syndrome represents a variant with predominant facial and cranial nerve involvement, although Miller Fisher and Guillain-Barré overlap syndromes can occur. Guillain-Barré spectrum syndromes have been thought to be rare among solid organ transplant recipients. We describe an immunocompromised patient with a liver transplant who presented with ophthalmoplegia and bulbar deficits. His symptoms rapidly progressed to a state of descending paralysis involving the diaphragm; he then developed acute respiratory failure and eventually developed quadriparesis. Electromyography and a nerve conduction study demonstrated a severe sensorimotor axonal polyneuropathy consistent with Miller Fisher variant Guillain-Barré syndrome. Despite several negative nasopharyngeal swabs for COVID-19 polymerase chain reaction, a serology for SARS-CoV-2 IgG was positive. He was diagnosed with Miller Fisher-Guillain-Barré overlap syndrome with rapid recovery following treatment with plasma exchange. Although Guillain-Barré is a rare complication in solid organ transplant recipients, this case highlights the importance of rapid diagnosis and treatment of neurologic complications in transplant patients. Furthermore, it demonstrates a possible case of neurological complications from COVID-19 infection.

Intraoperative Ventilation in the High-Risk Surgical Patient.

Postoperative pulmonary complications contribute to perioperative morbidity and mortality in addition to being associated with increased health care costs. In this review article, we outline risk factors for the development postoperative pulmonary complications, describe their impact on perioperative outcomes, and focus on the role of intraoperative ventilation strategies in decreasing postoperative pulmonary complications.

The Implementation and Outcomes of a Nurse-Run Extracorporeal Membrane Oxygenation Program, a Retrospective Single-Center Study.

Due to a shortage of perfusionists and increasing utilization of extracorporeal membrane oxygenation in the United States, many programs are training nurses as bedside extracorporeal membrane oxygenation specialists (i.e., nurse-run extracorporeal membrane oxygenation). Our objective was to evaluate if a nurse-run extracorporeal membrane oxygenation program has noninferior survival to discharge and complication rates compared with a perfusionist-run extracorporeal membrane oxygenation program. Additionally, to sought to describe increases in extracorporeal membrane oxygenation capacity and the potential for cost savings by implementing a nurse-run extracorporeal membrane oxygenation program.

Age-related incidence and outcomes of sepsis in California, 2008-2015.

PURPOSE: Sepsis remains amongst the most common causes of death worldwide. It has been described as a disease of the elderly, but contemporary data on risk factors and mortality is lacking. MATERIALS AND METHODS: Multi-center longitudinal cohort study using non-public, state of California data from January 1, 2008 to September 31, 2015. Patients with sepsis, severe sepsis, and septic shock were identified using ICD-9-CM diagnosis and procedure codes with age subgroups of 18-44, 45-64, 65-74, 75-84, and >85 years old. Descriptive statistics and a single direct logistic regression model were used to present data on incidence and mortality and to identify independent factors associated with mortality. RESULTS: Of 30,282,159 total inpatient encounters, 20,358,569 met inclusion criteria and 1,566,306 met sepsis criteria. Conditions associated with mortality included metastatic cancer, age, liver disease, residing in a care facility, and a gastrointestinal source of infection as well as fungal infection. Mortality in the >85-year-old subgroup with septic shock was 45.7%, lower than previously reported. CONCLUSION: Age remains an important sepsis risk factor, but other conditions correlated more closely with sepsis-associated death. Patients over 85 years of age suffering from septic shock may have a better chance of survival than previously thought.

E-cigarette use increases susceptibility to bacterial infection by impairment of human neutrophil chemotaxis, phagocytosis, and NET formation.

E-cigarettes are portrayed as safer relative to conventional tobacco. However, burgeoning evidence suggests that E-cigarettes may adversely affect host defenses. However, the precise mechanisms by which E-cigarette vapor alters innate immune cell function have not been fully elucidated. We determined the effects of E-cigarette exposure on the function and responses to infectious challenge of the most abundant innate immune cell, the neutrophil, using isolated human neutrophils and a mouse model of gram-negative infection. Our results revealed that human neutrophils exposed to E-cigarette vapor had 4.2-fold reductions in chemotaxis toward the bacterial cell-well component f-Met-Leu-Phe (P < 0.001). F-actin polarization and membrane fluidity were also adversely affected by E-cigarette vapor exposure. E-cigarette-exposed human neutrophils exhibited a 48% reduction in production of reactive oxygen species (ROS; P < 0.001). Given the central role of ROS in neutrophil extracellular trap (NET) production, NET production was quantified, and E-cigarette vapor exposure was found to reduce NETosis by 3.5-fold (P < 0.01); formulations with and without nicotine containing propylene glycol exhibiting significant suppressive effects. However, noncanonical NETosis was unaffected. In addition, exposure to E-cigarette vapor lowered the rate of phagocytosis of bacterial bioparticles by 47% (P < 0.05). In our physiological mouse model of chronic E-cigarette exposure and sepsis, E-cigarette vapor inhalation led to reduced neutrophil migration in infected spaces and a higher burden of Pseudomonas. These findings provide evidence that E-cigarette use adversely impacts the innate immune system and may place E-cigarette users at higher risk for dysregulated inflammatory responses and invasive bacterial infections.

Peripartum Cardiomyopathy: Current Options for Treatment and Cardiovascular Support.

Peripartum cardiomyopathy is a rare form of acute heart failure but the major cause of all deaths in pregnant patients with heart failure. Improved survival rates in recent years, however, emphasize the importance of early recognition and initiation of heart failure treatment. This article, therefore, attempts to raise awareness among cardiac and obstetric anesthesiologists as well as intensivists of this often fatal diagnosis. This review summarizes theories of the pathophysiology and outcome of peripartum cardiomyopathy. Based on the most recent literature, it further outlines diagnostic criteria and treatment options including medical management, mechanical circulatory support devices, and heart transplantation. Earlier recognition of this rare condition and a new generation of mechanical circulatory devices has contributed to the improved outcome. More frequently, patients in cardiogenic shock who fail medical management are successfully bridged to recovery on extracorporeal circulatory devices or survive with a long-lasting implantable ventricular assist device. The outcome of transplanted patients with peripartum cardiomyopathy, however, is worse compared to other recipients of heart transplants and warrants further investigation in the future.

Inhibition of Human Neutrophil Extracellular Trap (NET) Production by Propofol and Lipid Emulsion.

Uncontrolled bacteremia is a common and life threatening condition that can lead to sepsis and septic shock with significant morbidity and mortality. Neutrophil granulocytes, the most abundant phagocytic leukocyte of the innate immune system, play an essential role in capturing and killing invading pathogens. Their antimicrobial repertoire includes the formation of Neutrophil Extracellular Traps (NETs), chromatin-based, web-like structures of DNA that facilitate the capture and killing of bacteria. In sepsis, however, it has been suggested that the uncontrolled release of NETs worsens disseminated coagulation and promotes venous thrombosis. Here, we describe how clinically relevant concentrations of the commonly used sedative propofol as well as a lipid composition similar to the propofol carrier impair NET production by human neutrophils. Drugs commonly administered in the Intensive Care Unit (ICU) may impact the inflammatory response to either worsen or improve clinical outcomes and may therefore be considered for additional therapeutic effects if clinical studies confirm such findings.