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).

早期研究集中于感染性休克病理生理学（Am J Physiol 1988；Chest 1990）、内毒素血症（J Clin Invest 1989；J Exp Med 1989；Chest 1991；N Engl J Med 1993；Infect Immun 1996）和抗内毒素疗法（Antimicrob）化学药剂 1989；投资 1987；医药研究 1990；JAMA 1993；J Infect Dis 1994）。 研究了一氧化氮 (NO) 在感染性休克中的作用（Crit Care Med 1993；JAMA 1996）。非选择性NO合酶抑制剂有毒或缺乏益处（J Exp Med 1992；Crit Care Med 1998；Am J Respir Crit Care Med 1998）。受 LPS 攻击的志愿者中的 NO 被布洛芬阻断，但血压不受影响（J Pharmacol Exp Ther 1999）。 死亡风险影响脓毒症抗炎药物的治疗效果（Am J Respir Crit Care Med 2002）。 L-精氨酸对犬败血性休克是有害的（Crit Care Med 2006）。我们重新开发了犬败血症模型，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风险和氢化可的松疗效（重症监护医学 2008）。主动脉内球囊反搏可延长犬葡萄球菌肺炎引起的败血性休克的生存期（Crit Care Med 2009）。 美国危重疾病和损伤试验组 (USCIITG；http://www.usciitg.org/) 成立 (Crit Care Med 2009)。感染性休克的生存与早期和适当的抗生素有关（Crit Care Med 2010）。 抑制 p38 可改善心脏功能，但会加重小鼠肺炎的肺损伤和生存率 (J Trauma 2010)。液体和血管升压药对炭疽致死毒素大鼠模型有害（LeTx；Crit Care Med 2009）。在犬科动物中，添加 LeTx 后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率（Crit Care Med 2011）。对于犬肺炎，盐皮质激素有预防作用，而糖皮质激素在感染开始时有作用（Crit Care Med 2012）。皮质类固醇对于死亡风险高的败血症有益（重症监护医学 2012）。 替加环素与死亡率增加相关（Clin Infect Dis 2012）。粘菌素的使用确定了患有耐药细菌的重病人群（Clin Infect Dis 2015）。 使用气雾化葡萄球菌肠毒素 B (SEB) 小鼠模型，基因表达变化暗示多器官 IFN 反应 (PLoS One 2014)。 HPA 无反应和醛固酮水平与犬肺炎的不良预后相关（Am J Physiol Endocrinol Metab 2014）。 支持同意书错误地将低氧饱和度组描述为常规护理（PLoS One 2016）。 一名同种异体干细胞移植患者的弓形体脑炎并发 IRIS（骨髓移植 2016）。脑膜脑炎以埃博拉病毒为特征（Ann Intern Med 2016）。 脓毒症的诊断是主观的且可变的（Critical Care 2016）。感染性休克的发生率和死亡率的变化小于之前的估计（Chest 2017）。在坏死性筋膜炎和休克中，IVIG 未能降低死亡率（Clin Infect Dis 2017）。 2009 年至 2014 年期间脓毒症发病率和死亡率保持稳定（JAMA 2017）。 低剂量阿替普酶治疗次大面积肺栓塞可能对选定的患者有用（血液凝固纤溶2018）。对心血管疾病患者限制性输血与自由性输血的荟萃分析表明，死亡和冠状动脉事件的风险增加（Transfusion Med 2018）。 革兰氏阴性血流感染中的难治性耐药性 (DTR) 是导致死亡的独立因素（Clin Infect Dis 2018；Open Forum Infect Dis 2019）。脓毒症和器官功能障碍索赔数据的准确性差异限制了其有用性（Crit Care Med 2019）。使用示踪抗生素算法，XDR 革兰氏阴性感染的归因死亡率因比较药物和患者特征而异（Am J Infect Control 2019）。 在 PCT 指导的抗生素停药的荟萃分析中，仅在依从性差的低质量研究中看到了益处（Chest 2019）。在社区发病的脓毒症患者中，经验性抗生素不足和不必要的广泛使用都与死亡率相关（JAMA Netw Open 2020）。措施不足以确保比较有效性试验中的受试者接受常规而非异常护理（Crit Care Resusc 2020）。没有或次优治疗选择的 GNI 非常罕见，这凸显了非收入策略和创新试验设计的必要性 (Lancet Infect Dis 2020)。头孢他啶-阿维巴坦的使用量有所增加，而粘菌素的使用量相应减少 (Clin Infect Dis 2021)。在美国医院，五分之一的 BSI 患者接受了不一致的经验性抗生素治疗，这与死亡率相关。及早识别耐药病原体可能会改善人群水平的结果（Lancet Infect Dis 2021）。 克林霉素可改善侵袭性 A 组溶血性链球菌感染的结果，但不能改善非 A/B 组溶血性链球菌感染的结果 (Lancet Infect Dis 2021)。无细胞血红蛋白通过多种机制对脓毒症结果产生不利影响，并且可能代表一种新的治疗靶点（Am J Physiol Heart Circ Physiol 2021）。 尽管 COVID-19 的生存率有所改善，但医院病例数的激增对生存不利。加强预防以抑制激增并为激增的医院提供更好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，首次感染和再次感染之间的 SARS-CoV-2 医疗负担和疾病严重程度相似 (Clin Infect Dis 2022)。在嗜麦芽螺旋杆菌感染患者中，左氧氟沙星 (n = 823) 与 TMP-SMX (n = 758) 相比，显示出统计上相似的死亡风险 (Open Forum Infect Dis 2022)。 在顶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对照组。未能将当代实践纳入重症监护 CER 试验是一个普遍存在的设计缺陷（Crit Care Resusc 2022）。 严重的 COVID-19 与多器官衰竭和伴有微血栓的小血管病变有关。然而，抗血小板治疗（Ann Intern Med 评论 2022）和积极抗凝治疗并没有改善结果。我们正在研究内皮衰老作为 COVID-19 血管病变的一个可靶向机制。 感染性休克导致心室壁变化，无法用负荷或心肌坏死来解释（ACC 摘要 2022）。早期 EPI 并未加剧 LVEF 降低，相反 EPI 似乎具有心脏保护作用 (ACC 2022)。组织病理学和 CMRI 表明脓毒症引起的心脏损伤与水肿相关（ACC 摘要 2022）。随着水肿增加和 EF 恢复，急性左心室干质量损失发生，这与适应性修复过程一致。确定干物质的损失方式可能会阐明感染性休克中心脏损伤和修复的机制（AHA 摘要 2023）。 入院时的降钙素原 (PCT) 在排除 BSI 方面表现出较差的敏感性，并且似乎没有显着改变经验性抗生素的使用。入院时 PCT 的诊断和决策管理是必要的（Crit Care Med. 2023）。 有缺陷的重症监护 CER 试验设计可能会导致不合理的结论、损害知情同意、增加研究对象的风险，并破坏为当前实践提供信息的目标。结构良好的对照组和比较组是重症监护 CER 试验不可或缺的要素（Clin Trials 2023，待出版）。

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

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

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

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