Preclinical and Clinical Investigations of Severe Infection and Critical Illness

Clinical Center

Investigators

Linked publications, trials & patents

Abstract

Early studies in animals and patients 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), but 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, however, was safely blocked by ibuprofen (J Pharmacol Exp Ther 1999). Nonetheless, L-arginine, an NO substrate, was harmful in canine septic shock (Crit Care Med 2006) and the model was redeveloped to balance animal welfare and relevance (Am J Physiol Heart Circ Physiol 2007). Highly relevant to the investigation of anti-inflammatory agents in sepsis, risk-of-death affected the efficacy (Am J Respir Crit Care Med 2002; Intensive Care Med 2008). Intra-aortic balloon counter-pulsation prolonged survival in canine Staphylococcal pneumonia-induced septic shock (Crit Care Med 2009). Unlike septic shock, 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). Inhibiting p38 (J Trauma 2010) and heparin therapy (Crit Care Med 2011) both worsened survival in murine pneumonia. Corticosteroids in canines were only beneficial in high mortality sepsis (Crit Care Med 2012; Intensive Care Med 2012). In an aerosolized staphylococcal enterotoxin B (SEB) mouse model, gene-expression implicated a multiorgan IFN-response (PLoS One 2014). HPA unresponsiveness and aldosterone levels tracked with poor outcomes in canine pneumonia (Am J Physiol Endocrinol Metab 2014). The U.S. Critical Illness and Injury Trials Group (USCIITG) was founded (Crit Care Med 2009). In patients, septic shock survival was associated with early antibiotics (Crit Care Med 2010), but tigecycline compared to other antibiotics was associated with increased mortality (Clin Infect Dis 2012). Colistin use identified a severely ill patient population with drug-resistant bacteria (Clin Infect Dis 2015). SUPPORT consent forms incorrectly characterized the low oxygen saturation arm as usual care (PLoS One 2016). Toxoplasma 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 in patients was shown to be highly subjective and variable (Critical Care 2016). Septic shock incidence and mortality had changed little despite presumed advances (Chest 2017; JAMA 2017). In necrotizing fasciitis and shock, IVIG, a widely used adjunct, failed to decrease mortality (Clin Infect Dis 2017). Low dose alteplase for submassive pulmonary embolism was 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 independently contributed to death (Clin Infect Dis 2018; Open Forum Infect Dis 2019). Variation in claims data for sepsis and organ dysfunction limited their usefulness (Crit Care Med 2019). Attributable mortality for XDR gram-negative infections varied by comparator agents and patient characteristics (Am J Infect Control 2019). Both inadequate and unnecessarily broad empiric antibiotics were associated with mortality in community-onset sepsis (JAMA Network Open 2020). Measures have been inadequate to ensure that subjects in comparative effectiveness trials are not receiving unusual care (Crit Care Resusc 2020). GNIs with no or suboptimal treatment options underscores the necessity of non-revenue-based strategies and innovative trial designs (Lancet Infect Dis 2020). Ceftazidime-avibactam use increased, while colistin correspondingly declined (Clin Infect Dis 2021). One in 5 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 but not non-group A/B-hemolytic streptococcal infections (Lancet Infect Dis 2021). Among patients with S. maltophilia infections, levofloxacin (n = 823) had a statistically similar mortality risk compared to TMP-SMX (Open Forum Infect Dis 2022). In a meta-analysis of PCT-guided antibiotic discontinuation, benefit was only seen in low quality studies with poor adherence (Chest 2019). Procalcitonin (PCT)-on-admission demonstrated poor sensitivity in ruling out BSI and did not appear to alter empiric antibiotic usage. Diagnostic and decision-making stewardship of PCT-on-admission is warranted (Crit Care Med. 2023). 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). One-third of critical care comparative effectiveness research (CER) trials 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 2023) that leads to unsound conclusions, compromise informed consent, increase risks to research subjects. Well-constructed control and comparator arms are indispensable elements of critical care CER trials (Clin Trials 2024). An update of our 2018 meta-analysis of transfusion practices likewise found harm when restrictive thresholds are used for patients with CVD, hospitalized for either ACS or noncardiac reasons (Circ Cardiovasc Qual Outcomes. 2024). Surges in COVID-19 hospital caseloads were detrimental to survival. Bolstering prevention to suppress surges and better support for surging hospitals may save lives (Ann Intern Med 2021). SARS-CoV-2 healthcare burden and illness severity were similar between index and reinfection encounters (Clin Infect Dis 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. Endothelial senescence may represent a targetable mechanism of COVID-19 vasculopathy (Vascular Discovery AHA abstracts 2025). Cardiac dysfunction during sepsis is not primarily due to elevated endogenous or exogenous catecholamines nor decreased microvascular perfusion-induced ischemia (ACC abstract 2022). LVEF depression was not exacerbated by early epinephrine. However, epinephrine itself has potentially harmful long-lasting ischemic effects during sepsis including impaired cardiac microvascular perfusion that persists after stopping the infusion (J Am Heart Assoc. 2024). 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; J Am Heart Assoc 2024). Septic shock diastolic dysfunction, not decreased ejection fraction, was associated with mortality (bioRxiv 2024; IARS and SOCCA abstract 2025; ACP abstract 2025). A low LVEDV indicates persistent unrepairable ultrastructure damage with worsening wall compliance and poorer outcomes. LVEDV dilation is a sign of near-full recovery of ultrastructure injury, augmenting wall compliance and improving outcomes (bioRxiv 2025).