Prognostic & Therapeutic Implications of Breathing Patterns in Acute Lung Injury

预后

• 批准号: 8597998
• 负责人: Frank Joseph Jacono
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597998
• 关键词: Acute Lung Injury; Address; Adoption; Animal Model; Biological; Biological Markers; Bleomycin; Breathing; Caring; Categories; Cessation of life; Characteristics; Chemicals; Clinical; Clinical Research; Clinical Trials; Comorbidity; Complex; Confounding Factors (Epidemiology); Critical Care; Data; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Disease model; Disease regression; Economic Burden; Ensure; Environmental air flow; Excision; Exposure to; Foundations; Gases; Goals; Health; Hospitalization; Hospitals; Human; Infection; Inhalation Exposure; Injury; Intensive Care Units; Knowledge; Lead; Link; Lung; Lung diseases; Measurement; Measures; Mechanical ventilation; Mechanics; Modeling; Outcome; Outcome Measure; Outcome Study; Patient Triage; Patients; Pattern; Phosgene; Physiological; Pneumonia; Pulmonary Fibrosis; Pulmonary Heart Disease; Qualifying; Receiver Operating Characteristics; Recovery; Rehabilitation therapy; Research; Research Design; Research Methodology; Research Personnel; Resolution; Resources; Respiratory Failure; Respiratory physiology; Ricin; Risk; Risk Assessment; Rodent; Rodent Model; Services; Severities; Severity of illness; Signal Transduction; Staphylococcal Enterotoxin B; Structure; Systems Analysis; Techniques; Therapeutic; Tidal Volume; Toxin; Translating; Traumatic Brain Injury; Triage; United States Department of Veterans Affairs; Ventilator; Ventilator Weaning; War; Weaning; Woman; Work; aerosolized; base; combat; diagnostic accuracy; high risk; improved; indexing; injured; innovation; lung injury; men; mortality; neuroregulation; novel; novel strategies; patient population; preclinical study; prognostic; rapid diagnosis; relating to nervous system; research study; respiratory; success

DESCRIPTION (provided by applicant): Rationale: Each year 200,000 cases of Acute Lung Injury (ALI) result in 75,000 deaths. Mechanical ventilation is needed to manage a subset of these patients but causes further injury termed ventilator- associated lung injury (VALI). Often these patients require care in an intensive care unit (ICU), contributing to a heavy economic burden as critical care consumes approximately 1% of the U.S. gross domestic product. Objectives: Our long-term goals include: 1) development of respiratory biomarkers based on breathing pattern variability that identify high-risk patients. These indices would facilitate appropriate triage of patients who need advanced care thereby improving resource utilization, as well as allow more rapid initiation of therapies that could minimize the need for mechanical ventilation; and 2) development of novel ventilatory strategies based on optimizing the parameters of biologically variable ventilation (BVV) to limit changes in breathing patterns, minimize VALI and improve ventilator weaning. In the present application we propose pre- clinical studies in well-validated animal models. While the analytical techniques for measuring breathing pattern variability are amenable to human studies, preliminary study in disease models free of co-morbidities and other confounding variables is the best approach before undertaking more extensive studies in humans. Ultimately, knowledge gained will be used to develop measures of pattern variability that will provide diagnostic and predictive information for risk assessment in humans, in addition to forming the foundation for new approaches to ventilator management of cardiopulmonary diseases leading to respiratory failure. Research Design and Methods: The present application addresses the following two questions: 1) can measurements of breathing pattern variability predict disease progression or regression in ALI and VALI; and 2) does the addition of biological variability on a breath-by-breath basis maintain normal breathing pattern variability, minimize VALI, and thereby promote successful weaning from the ventilator? Studies in Aim 1 will directly address the hypothesis that changes in the underlying structure of breathing pattern variability reflect the severity of lung injury, and are predictive of progression or resolution of lung injury. Well established and validated rodent models of lung injury (bleomycin-instillation and high tidal volume ventilation) will be used. Experiments will correlate temporal patterns of breathing with lung injury categories related to mechanism and clinical impact. Findings will be used to develop multivariate models for diagnosing lung injury and predicting resolution. Receiver operating characteristic (ROC) curve analysis will be used to compare the diagnostic accuracy of different indices of breathing pattern variability. Experiments in Aim 2 will determine if a strategy of mechanical ventilation that includes biologic variability can limit the duration of respiratory failure and improve ventilator weaning. BVV will be compared to conventional mechanical ventilation in the settings of VALI and pre-existing chemically-induced ALI in rodents. Outcome measures will include ability to maintain adequate spontaneous ventilation after removal of ventilator support, as well as lung injury severity and return of baseline breathing patterns after weaning from the ventilator. Significance: The proposed research is innovative as changes in variability of respiratory patterns with ALI and VALI are not appreciated, and a complex systems analysis approach has not previously been applied to these important clinical conditions. We expect the outcomes of these studies will lead to the development of new ventilation strategies that incorporate biological variability, and will guide the development of novel physiologic markers that correlate with illness severity and outcome. While initially applied in the ICU, these approaches will be easily applied in other settings identifying patients in need of a higher level of care or more intensive therapy.

描述（由申请人提供）： 理由：每年20万例急性肺损伤（ALI）导致75，000例死亡。需要机械通气来管理这些患者的子集，但会导致称为呼吸机相关肺损伤（VALI）的进一步损伤。这些患者通常需要在重症监护室（ICU）中接受护理，造成沉重的经济负担，因为重症监护消耗了美国国内生产总值的约1%。目的：我们的长期目标包括：1）基于呼吸模式变异性开发呼吸生物标志物，以识别高风险患者。这些指标将有助于对需要高级护理的患者进行适当的分诊，从而提高资源利用率，并允许更快速地启动治疗，从而最大限度地减少对机械通气的需求; 2）基于优化生物可变通气（BVV）参数的新治疗策略的开发，以限制呼吸模式的变化，最大限度地减少VALI并改善呼吸机脱机。在本申请中，我们提出在充分验证的动物模型中进行临床前研究。虽然测量呼吸模式变异性的分析技术适用于人体研究，但在进行更广泛的人体研究之前，最好先对无合并症和其他混杂变量的疾病模型进行初步研究。最终，所获得的知识将用于开发模式变异性的测量，这些测量将为人类风险评估提供诊断和预测信息，此外还将为导致呼吸衰竭的心肺疾病的呼吸机管理新方法奠定基础。研究设计和方法：本申请解决了以下两个问题：1）呼吸模式变异性的测量是否能够预测ALI和VALI中的疾病进展或消退;以及2）在逐个呼吸的基础上增加生物变异性是否维持正常的呼吸模式变异性，使VALI最小化，从而促进成功地从呼吸机脱机？目标1中的研究将直接解决以下假设：呼吸模式变异性的基础结构变化反映了肺损伤的严重程度，并可预测肺损伤的进展或消退。将使用完善且经验证的啮齿动物肺损伤模型（博来霉素滴注和大潮气量通气）。实验将把呼吸的时间模式与与机制和临床影响相关的肺损伤类别相关联。研究结果将用于开发诊断肺损伤和预测解决方案的多变量模型。受试者工作特征（ROC）曲线分析将用于比较呼吸模式变异性的不同指标的诊断准确性。目标2中的实验将确定包括生物变异性的机械通气策略是否可以限制呼吸衰竭的持续时间并改善呼吸机脱机。在VALI和啮齿动物中既存化学诱导的ALI的情况下，将BVV与传统机械通气进行比较。结局指标将包括移除呼吸机支持后维持充分自主通气的能力，以及肺损伤严重程度和脱离呼吸机后恢复基线呼吸模式。重要性：拟议的研究是创新的，因为ALI和VALI的呼吸模式的可变性变化并不受欢迎，并且复杂的系统分析方法以前没有应用于这些重要的临床条件。我们预计这些研究的结果将导致新的通气策略的发展，包括生物学变异性，并将指导与疾病严重程度和结果相关的新的生理标志物的发展。虽然最初应用于ICU，但这些方法将很容易应用于其他环境，以确定需要更高水平护理或更密集治疗的患者。