Preclinical and Clinical Investigations of Severe Infection and Critical Illness

Clinical Center

Investigators

Linked publications & trials

Abstract

Early studies focused on septic shock pathophysiology (Am J Physiol 1988; Chest 1990), endotoxemia (J Clin Invest 1989; J Exp Med 1989; Chest 1991; N Engl J Med 1993; Infect Immun 1996), and anti-endotoxin therapies (Antimicrob Agents Chemother 1989; J Clin Invest 1987; Pharm Res 1990; JAMA 1993; J Infect Dis 1994). Nitric oxide (NO) was investigated in septic shock (Crit Care Med 1993; JAMA 1996). Non-selective NO synthase inhibitors were toxic or lacked benefit (J Exp Med 1992; Crit Care Med 1998; Am J Respir Crit Care Med 1998). NO in LPS-challenged volunteers was blocked by ibuprofen, but BP was unaffected (J Pharmacol Exp Ther 1999). Risk of death affected the therapeutic efficacy of anti-inflammatory agents in sepsis (Am J Respir Crit Care Med 2002). L-arginine in canine septic shock was harmful (Crit Care Med 2006). Our canine sepsis model was redeveloped to balance animal welfare and relevance (Am J Physiol Heart Circ Physiol 2007). Risk of death and hydrocortisone efficacy were investigated in a mouse pneumonia model (Intensive Care Med 2008). Intra-aortic balloon counterpulsation prolonged survival in canine Staphylococcal pneumonia-induced septic shock (Crit Care Med 2009). The U.S. Critical Illness and Injury Trials Group (USCIITG; http://www.usciitg.org/) was founded (Crit Care Med 2009). Septic shock survival was associated with early and appropriate antibiotics (Crit Care Med 2010). Inhibiting p38 improved cardiac function but worsened lung injury and survival in murine pneumonia (J Trauma 2010). Fluids and vasopressors were harmful in a rat model of anthrax lethal toxin (LeTx; Crit Care Med 2009). In canines, edema toxin increased mortality when added to LeTx (J Infect Dis 2010). Heparin failed to improve lung injury or survival in E. coli pneumonia (Crit Care Med 2011). In canine pneumonia, mineralocorticoid was beneficial prophylactically, while glucocorticoid was beneficial at the onset of infection (Crit Care Med 2012). Corticosteroids were beneficial in sepsis with a high risk of death (Intensive Care Med 2012). Tigecycline was associated with increased mortality (Clin Infect Dis 2012). Colistin use identified a severely ill population with drug-resistant bacteria (Clin Infect Dis 2015). Using an aerosolized staphylococcal enterotoxin B (SEB) mouse model, gene-expression changes implicated a multiorgan IFN-response (PLoS One 2014). HPA unresponsiveness and aldosterone levels were associated with poor outcomes in canine pneumonia (Am J Physiol Endocrinol Metab 2014). SUPPORT consent forms incorrectly characterized the low oxygen saturation arm as usual care (PLoS One 2016). Toxoplasmosis encephalitis was complicated by IRIS in an allogeneic stem cell transplant patient (Bone Marrow Transplant 2016). Meningoencephalitis was characterized in Ebola (Ann Intern Med 2016). Diagnosing sepsis is subjective and variable (Critical Care 2016). Septic shock incidence and mortality changed less than previously estimated (Chest 2017). In necrotizing fasciitis and shock, IVIG failed to decrease mortality (Clin Infect Dis 2017). Sepsis incidence and death rate was stable between 2009-2014 (JAMA 2017). Low dose alteplase for submassive pulmonary embolism might be useful in selected patients (Blood Coagul Fibrinolysis 2018). Meta-analysis of restrictive vs. liberal transfusion in patients with cardiovascular disease demonstrated an increased risk of death and coronary events (Transfusion Med 2018). Difficult to Treat Resistance (DTR) in gram-negative bloodstream infections was an independent contributor to death (Clin Infect Dis 2018; Open Forum Infect Dis 2019). Variation in the accuracy of claims data for sepsis and organ dysfunction limited their usefulness (Crit Care Med 2019). Using tracer antibiotic algorithms, attributable mortality for XDR gram-negative infections varied by comparator agents and patient characteristics (Am J Infect Control 2019). In a meta-analysis of PCT-guided antibiotic discontinuation, benefit was only seen in low quality studies with poor adherence (Chest 2019). In patients with community-onset sepsis, both inadequate and unnecessarily broad empiric antibiotics were associated with mortality (JAMA Netw Open 2020). Measures have been inadequate to ensure that subjects in comparative effectiveness trials are receiving usual and not unusual care (Crit Care Resusc 2020). The rarity of GNIs with no or suboptimal treatment options underscores the necessity for non-revenue-based strategies and innovative trial designs (Lancet Infect Dis 2020). Ceftazidime-avibactam use has increased, while colistin has correspondingly declined (Clin Infect Dis 2021). One in 5 patients with BSIs in US hospitals received discordant empirical antibiotic therapy, which was associated with mortality. Early identification of resistant pathogens will likely improve population-level outcomes (Lancet Infect Dis 2021). Clindamycin improves the outcome of invasive group A-hemolytic streptococcal, but not non-group A/B-hemolytic streptococcal infections (Lancet Infect Dis 2021). Cell-free hemoglobin adversely impacts sepsis outcomes through more than one mechanism and could represent a novel therapeutic target (Am J Physiol Heart Circ Physiol 2021). Despite improvements in COVID-19 survival, surges in hospital caseloads were detrimental to survival. Bolstering prevention to suppress surges and better support for surging hospitals may save lives (Ann Intern Med 2021). In an inpatient and outpatient study, SARS-CoV-2 healthcare burden and illness severity were similar between index and reinfection encounters (Clin Infect Dis 2022). Among patients with S maltophilia infections, levofloxacin (n = 823) displayed statistically similar mortality risk compared to TMP-SMX (n = 758) (Open Forum Infect Dis 2022). One-third of critical care comparative effectiveness research (CER) trials published in premier journals did not include a designated control arm representative of contemporary practices. Failure to incorporate contemporary practices into critical care CER trials is a widespread design weakness (Crit Care Resusc 2022). Severe COVID-19 is associated with multiorgan failure and small vessel vasculopathy with microthrombi. However, antiplatelet therapy (Ann Intern Med commentary 2022) and aggressive anticoagulation have not improved outcome. We are examining endothelial senescence as a targetable mechanism of COVID-19 vasculopathy. Septic shock results in ventricular wall changes not explained by loading or myocardial necrosis (ACC abstract 2022). LVEF depression was not exacerbated by early EPI, rather EPI appeared cardioprotective (ACC 2022). Sepsis-induced cardiac injury was associated with edema by histopathology and CMRI (ACC abstract 2022). Acute LV dry mass loss occurred as edema increased and EF recovered, consistent with an adaptive, reparative process. Determining how dry mass is lost may clarify mechanisms of cardiac injury and repair in septic shock (AHA abstract 2023). Procalcitonin (PCT)-on-admission demonstrated poor sensitivity in ruling out BSI and did not appear to meaningfully alter empiric antibiotic usage. Diagnostic and decision-making stewardship of PCT-on-admission is warranted (Crit Care Med. 2023). Flawed critical care CER trial designs can lead to unsound conclusions, compromise informed consent, increase risks to research subjects, and undermine the goal of informing current practice. Well-constructed control and comparator arms are indispensable elements of critical care CER trials (Clin Trials 2023, in press).