Preclinical and Clinical Investigations of Severe Infection and Critical Illness

严重感染和危重疾病的临床前和临床研究

• 批准号: 10923694
• 负责人: ROBERT L DANNER
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10923694
• 关键词: 2019-nCoV; Acute; Adherence; Admission activity; Adrenal Cortex Hormones; Affect; Aldosterone; Algorithms; Allogenic; Alteplase; Animal Model; Animal Welfare; Anti-Inflammatory Agents; Antibiotic Therapy; Antibiotics; Anticoagulation; Aorta; Arginine; Blood; Blood Platelets; Bone Marrow Transplantation; COVID-19; COVID-19 survivors; Canis familiaris; Cardiovascular Diseases; Cardiovascular system; Caring; Ceftazidime; Cell Culture System; Cells; Cessation of life; Characteristics; Chest; Clindamycin; Colistin; Communities; Comparative Effectiveness Research; Comparison arm; Consent Forms; Counterpulsation; Critical Care; Critical Illness; Data; Databases; Death Rate; Decision Making; Diagnosis; Diagnostic; Dose; Dryness; Early identification; Ebola; Edema; Elements; Encephalitis; Endothelium; Endotoxemia; Endotoxins; Epidemiology; Equilibrium; Escherichia coli; Etiology; Failure; Fibrinolysis; Functional disorder; Gene Expression; Glucocorticoids; Goals; Healthcare; Heart; Heart Injuries; Hemoglobin; Heparin; Histopathology; Hospitals; Hydrocortisone; Ibuprofen; Incidence; Infection; Inflammation; Informed Consent; Injury; Inpatients; Intensive Care; Interferons; Internships; Intravenous Immunoglobulins; Investigation; Investments; Journals; Left Ventricular Ejection Fraction; Levaquin; Liquid substance; Measures; Meningoencephalitis; Mental Depression; Meta-Analysis; Mineralocorticoids; Modeling; Morbidity - disease rate; Multiple Organ Failure; Mus; Myocardial; Myocardial Infarction; Necrosis; Necrotizing fasciitis; Nitric Oxide; Nitric Oxide Synthetase Inhibitor; Organ; Outcome; Outpatients; Oxygen; Patient Selection; Patients; Pneumonia; Population; Prevention; Public Health; Published Comment; Publishing; Pulmonary Embolism; Rattus; Research Subjects; Resistance; Risk; Sepsis; Septic Shock; Severity of illness; Shock; Staphylococcal Enterotoxin B; Staphylococcal Pneumonia; Stem cell transplant; Stenotrophomonas maltophilia; Streptococcal Infections; Streptococcus; Stroke; Supportive care; Syndrome; Therapeutic; Thrombus; Toxin; Toxoplasmosis; Tracer; Transfusion; Transplant Recipients; Trauma; Treatment Efficacy; Trimethoprim-Sulfamethoxazole; Variant; Vascular Diseases; Vasoconstrictor Agents; Ventricular; aerosolized; anthrax lethal factor; arm; attributable mortality; cardiac repair; cardioprotection; care burden; clinical investigation; comparative effectiveness trial; coronary event; design; drug resistant bacteria; heart function; high risk; improved; improved outcome; indexing; innovation; lethal factor; lung injury; mortality; mortality risk; mouse model; new therapeutic target; p38 Mitogen Activated Protein Kinase; pandemic disease; pathogen; pneumonia model; pre-clinical; procalcitonin; prophylactic; reparative process; response; senescence; severe COVID-19; severe injury; tigecycline; treatment as usual; trial design; volunteer

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).

早期研究的重点是败血性休克病理生理学（Am J Physiol 1988; Chest 1990），内毒素血症（J Clin Invest 1989; J Exp Med 1989; Jelts 1989; Chest 1991; n Engl J Med 1993; Infect Immun 1996; Infi-dyotoxin疗法and antimicrob tentent Chine otherother Chemother Chemother Chin 1989; J Clin 1989; J Clin Invest 1987; Pharm Res inst; Jama; Jama; Jama; Jama; 一氧化氮（NO）在败血性休克中进行了研究（Crit Care Med 1993； Jama 1996）。非选择性的NO合酶抑制剂是有毒或缺乏益处的（J Exp Med 1992； Crit Care Med 1998； Am J呼吸症Carit Care Med 1998）。布洛芬（BP）阻止了LPS挑战者的志愿者，但BP不受影响（J Pharmacol Exp Ther 1999）。 死亡的风险影响了抗炎药在败血症中的治疗功效（Am J Respir Crit Care Med 2002）。犬败血性休克中的L-精氨酸有害（Crit Care Med 2006）。我们的犬类败血症模型经过重新开发，以平衡动物福利和相关性（Am J Physiol Heart Circ Physiol 2007）。在小鼠肺炎模型中研究了死亡和氢化可的松疗效的风险（重症监护MED 2008）。在犬葡萄球菌肺炎引起的败血性休克中，可通用的气球内脉冲长期生存（Crit Care Med 2009）。 美国重症疾病和伤害试验小组（USCIITG; http://www.usciitg.org/）成立了（Crit Care Med 2009）。败血性休克存活与早期和适当的抗生素有关（Crit Care Med 2010）。 抑制p38改善了心脏功能，但在鼠肺炎的肺损伤和生存恶化（J Trauma 2010）。在炭疽致死毒素的大鼠模型中，液体和加压剂有害（Letx； Crit Care Med 2009）。在犬类中，添加到LETX时，水肿毒素会增加死亡率（J Infect Dis 2010）。肝素未能改善大肠杆菌肺炎的肺损伤或生存（Crit Care Med 2011）。在犬类肺炎中，矿物皮质激素是预防性的，而糖皮质激素在感染开始时是有益的（Crit Care Med 2012）。皮质类固醇对败血症是有益的，死亡风险高（重症监护医学，2012年）。 Tigecycline与死亡率的增加有关（Clin Infect Dis 2012）。 Colistin使用确定了患有耐药细菌的严重疾病人群（Clin Infect DIS 2015）。 使用雾化的葡萄球菌肠毒素B（SEB）小鼠模型，基因表达变化暗示了多机IFN反应（PLOS ONE 2014）。 HPA无反应性和醛固酮水平与犬肺炎的结局差有关（AM J Physiol Endobinol Metab 2014）。 支持同意书不正确地表征了低氧饱和臂的表征（PLOS One 2016）。 同种异体干细胞移植患者中虹膜复杂的弓形虫病脑炎复杂（骨髓移植2016）。脑膜脑炎在埃博拉病毒中的特征是（Ann Intern Med 2016）。 诊断败血症是主观和可变的（重症监护2016）。败血性休克发生率和死亡率的变化少于先前估计的（Chest 2017）。在坏死性筋膜炎和休克中，IVIG无法降低死亡率（Clin Infect Dis 2017）。败血症发生率和死亡率在2009 - 2014年之间是稳定的（JAMA 2017）。 下兼性肺栓塞的低剂量高齿酶可能对选定的患者有用（血液辅助纤维蛋白溶解2018）。心血管疾病患者的限制性与自由输血的荟萃分析表明，死亡和冠状动脉事件的风险增加（Theffufie Med 2018）。 在革兰氏阴性血液感染中难以治疗耐药性（DTR）是死亡的独立贡献者（Clin Infect Dis 2018；开放论坛Infect Dis 2019）。败血症和器官功能障碍的索赔数据准确性的差异限制了其用途（Crit Care Med 2019）。使用示踪剂抗生素算法，XDR革兰氏阴性感染的可归因死亡率因比较剂和患者特征而变化（AM J Infect Control 2019）。 在对PCT引导的抗生素中断的荟萃分析中，仅在依从性较差的低质量研究中才能看到益处（Chest 2019）。在社区发作败血症的患者中，既不足够的和不必要的宽实验抗生素都与死亡率有关（JAMA NETW开放2020年）。措施不足以确保比较有效试验中的受试者接受常规而不是异常护理（Crit Care Resusc 2020）。 GNI的稀有性具有没有或次优的治疗方案，强调了非基于收入的策略和创新试验设计的必要性（Lancet Infect DIS 2020）。 Ceftazidime-avibactam的使用增加了，而大肠菌素的使用相应下降（Clin Infect DIS 2021）。美国医院中BSIS的五分之一患者接受了与死亡率有关的不一致的经验抗生素疗法。抗性病原体的早期鉴定可能会改善人口水平的结果（柳叶刀感染DIS 2021）。 克林霉素改善了侵入性A型A-溶质性链球菌的结果，但不能改善非组A/B-溶血性链球菌感染（Lancet Infect Dis 2021）。无细胞的血红蛋白通过多种机制不利地影响败血症的结果，并且可以代表一种新型的治疗靶点（Am J Physiol Heart Circ Physiol 2021）。 尽管Covid-19的生存率有所改善，但医院案件的涌现对生存有害。加强预防以抑制潮流和更好地支持医院的支持可能会挽救生命（Ann Intern Med 2021）。在一项住院和门诊研究中，指数和再感染相遇之间的SARS-COV-2医疗保健负担和疾病严重程度相似（Clin Infect DIS 2022）。与TMP-SMX（n = 758）相比，左氧氟沙星（n = 823）的麦芽菌感染患者（n = 823）在统计上具有相似的死亡率风险（n = 758）（开放论坛感染2022）。 在高级期刊上发表的重症监护比较有效性研究（CER）试验中有三分之一不包括代表当代实践的指定控制部门。未能将当代实践纳入重症监护CER试验是一种广泛的设计弱点（Crit Care Resusc 2022）。 严重的COVID-19与具有微骨的多器官衰竭和小血管脉管病有关。然而，抗血小板疗法（Ann Intern Med评论2022）和攻击性抗凝治疗尚未改善预后。我们正在研究内皮衰老，作为COVID-19血管病的目标机制。 败血性休克导致心室壁变化无法通过负荷或心肌坏死来解释（ACC Abstract 2022）。 EPI早期并没有加剧LVEF抑郁症，而EPI则表现为心脏保护作用（ACC 2022）。败血症引起的心脏损伤与组织病理学和CMRI有关（ACC摘要2022）。急性LV干质量损失随着水肿的增加并恢复EF，与适应性的，修复过程一致。确定干质量如何丢失可能会阐明败血性休克中心脏损伤和修复的机制（AHA摘要2023）。 促甲基毒素（PCT） - 在排除BSI方面表现出较差的敏感性，并且似乎没有有意义地改变经验性抗生素的用法。有必要对PCT进行诊断和决策管理（Crit CareMed。2023）。 有缺陷的重症监护CER试验设计可能会导致结论不大，妥协知情同意，增加研究对象的风险，并破坏为当前实践提供信息的目标。结构良好的控制和比较臂是重症监护CER试验不可或缺的元素（Clin试验2023，印刷中）。

项目成果

Therapeutic Drug Monitoring and Genotypic Screening in the Clinical Use of Voriconazole.

• DOI: 10.1007/s12281-015-0219-0
• 发表时间: 2015-06
• 期刊: Current fungal infection reports
• 影响因子: 1.4
• 作者: Moriyama B;Kadri S;Henning SA;Danner RL;Walsh TJ;Penzak SR
• 通讯作者: Penzak SR

Bundled care for septic shock: an analysis of clinical trials.

• DOI: 10.1097/ccm.0b013e3181cb0ddf
• 发表时间: 2010-02
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Barochia AV;Cui X;Vitberg D;Suffredini AF;O'Grady NP;Banks SM;Minneci P;Kern SJ;Danner RL;Natanson C;Eichacker PQ
• 通讯作者: Eichacker PQ

Persistence of Pseudomonas aeruginosa in a pulmonary nodule with late relapse.

肺结节中铜绿假单胞菌的持续存在，且晚期复发。

• DOI: 10.1111/tid.12253
• 发表时间: 2014
• 期刊: Transplant infectious disease : an official journal of the Transplantation Society
• 作者: Ronkainen,S;Xie,Y;Battiwalla,M;Barrett,AJ;Stock,F;Dekker,JP;Danner,RL
• 通讯作者: Danner,RL

ACP Journal Club: review: in sepsis, the effect of resuscitation with crystalloid and colloid fluids on mortality varies.

ACP 期刊俱乐部：评论：在脓毒症中，晶体液和胶体液复苏对死亡率的影响各不相同。

• DOI: 10.7326/0003-4819-161-10-201411180-02012
• 发表时间: 2014
• 期刊: Annals of internal medicine
• 影响因子: 39.2
• 作者: Kadri,SameerS;Danner,RobertL
• 通讯作者: Danner,RobertL

Stability of isoniazid injection in i.v. solutions.

异烟肼注射液静脉注射的稳定性

• DOI: 10.2146/ajhp170268
• 发表时间: 2018
• 期刊: American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists
• 作者: Lee,JunH;Moriyama,Brad;Henning,StaceyA;Danner,RobertL;Walsh,ThomasJ;Penzak,ScottR;Grimes,GeorgeJ;Potti,GopalK
• 通讯作者: Potti,GopalK