Altering Sedation Paradigms to Improve Brain Injury and Survival in Severe Sepsis

改变镇静模式以改善严重脓毒症的脑损伤和生存率

基本信息

项目摘要

DESCRIPTION (provided by applicant): The need for mechanical ventilation (MV) secondary to sepsis is the leading cause of admission to the intensive care unit, often necessitating sedation for patient safety and comfort. Recently, we have learned that these sedative medications contribute to iatrogenic injury, such as prolonging ventilator time and ICU length of stay and exacerbating acute brain dysfunction. This acute brain dysfunction, manifested as delirium and coma, occurs in 50%-70% of MV septic patients and is a significant contributor not only to death but also to functional and cognitive decline, which can persist for years after recovery of lung and other organ function, levying significant costs to patients and society. Despite advances in the management of acute respiratory failure and sepsis, few clinical trials have examined the effects that supportive therapies, like sedation, may have on both short- and long-term outcomes in this vulnerable population. The gamma-aminobutyric acid (GABA)-ergic benzodiazepines, in particular, have been shown to increase brain dysfunction, promote infection, and prolong MV. Therefore, the short-acting GABA-ergic sedative propofol and the alpha2 agonist dexmedetomidine are becoming widely used to sedate septic MV patients. There are only a few randomized trials, however, to guide clinicians when selecting between these and other sedatives, and none have explored the mechanisms underlying the differences in outcomes, though some data indicate that GABA-ergic and alpha2 agonist agents have very different effects on innate immunity, apoptosis, arousability, and respiratory drive. In early animal and human studies, dexmedetomidine had more anti-inflammatory effects than the GABA-ergic agents; dexmedetomidine improved bacterial clearance, whereas propofol impaired it. In addition, sedation with dexmedetomidine instead of benzodiazepines reduces delirium by 20%-30% and improves arousability, cognition, and attentiveness in ventilated patients. Alpha2 agonists induce unconsciousness at the brainstem- more akin to natural sleep-which may improve autonomic function and immunity. All these factors converge to suggest that sedation with an alpha2 agonist rather than a GABAergic agent may improve outcomes, including brain function, MV, and survival, for septic MV patients. We therefore propose the MENDS II (Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure) study, in which we will test the hypotheses that sedation of MV severely septic patients with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will (Aim 1A) increase days alive without delirium or coma, (Aim 1B) increase ventilator-free days, (Aim 2A) improve 90-day survival, (Aim 2B) decrease long-term cognitive impairment, and (Aim 3) reduce the pro-inflammatory cytokine cascade following sepsis. We will randomize 530 ventilated, severely septic patients requiring goal-directed sedation with dexmedetomidine or propofol, giving the study 90% power to detect a difference of 1.5 delirium/coma-free days and an absolute difference in mortality of 10% between the two groups.
描述(由申请人提供): 脓毒症继发的机械通气 (MV) 需求是进入重症监护病房的主要原因,通常需要镇静以保证患者的安全和舒适。最近,我们了解到这些镇静药物会导致医源性损伤,例如延长呼吸机时间和 ICU 住院时间,并加剧急性脑功能障碍。这种急性脑功能障碍表现为谵妄和昏迷,发生在 50%-70% 的 MV 脓毒症患者中,不仅导致死亡,而且导致功能和认知能力下降,这种情况在肺和其他器官功能恢复后可能持续数年,给患者和社会带来巨大成本。尽管在急性呼吸衰竭和脓毒症的治疗方面取得了进展,但很少有临床试验研究镇静等支持疗法可能对这一弱势群体的短期和长期结果的影响。尤其是γ-氨基丁酸 (GABA) 能苯二氮卓类药物已被证明会增加脑功能障碍、促进感染并延长 MV。因此,短效 GABA 镇静剂异丙酚和 α2 激动剂右美托咪定正广泛用于脓毒症 MV 患者的镇静。然而,只有少数随机试验指导临床医生在这些镇静剂和其他镇静剂之间进行选择,并且没有探索结果差异背后的机制,尽管一些数据表明 GABA 能药物和 α2 激动剂药物对先天免疫、细胞凋亡、觉醒和呼吸动力有非常不同的影响。在早期的动物和人体研究中,右美托咪定比 GABA 能药物具有更强的抗炎作用。右美托咪定可改善细菌清除率,而异丙酚则会削弱细菌清除率。此外,用右美托咪定代替苯二氮卓类药物镇静可减少 20%-30% 的谵妄,并提高通气患者的唤醒能力、认知能力和注意力。 Alpha2 激动剂会诱导脑干失去意识(更类似于自然睡眠),这可能会改善自主功能和免疫力。所有这些因素共同表明,使用 α2 激动剂而不是 GABA 能药物进行镇静可能会改善脓毒症 MV 患者的预后,包括脑功能、MV 和生存率。因此,我们提出 MENDS II(最大限度地提高急性呼吸衰竭脓毒症患者的镇静效果并减少神经功能障碍和死亡率)研究,其中我们将测试以下假设:使用 α2 激动剂(右美托咪定)而不是 GABA 能药物(异丙酚)对 MV 严重脓毒症患者进行镇静将(目标 1A)增加无谵妄或谵妄的存活天数。 昏迷,(目标 1B)增加无需呼吸机的天数,(目标 2A)提高 90 天生存率,(目标 2B)减少长期认知障碍,以及(目标 3)减少脓毒症后的促炎细胞因子级联反应。我们将随机抽取 530 名需要使用右美托咪定或丙泊酚进行目标导向镇静的通气、严重脓毒症患者,使研究有 90% 的功效检测到两组之间 1.5 个无谵妄/昏迷天数的差异以及 10% 的死亡率绝对差异。

项目成果

期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Paying it forward: Four-year analysis of the Eastern Association for the Surgery of Trauma Mentoring Program.
向前迈进:东部创伤外科协会指导计划的四年分析。
  • DOI:
    10.1097/ta.0000000000001493
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Zakrison,TanyaL;Polk,TravisM;Dixon,Rachel;Ekeh,AkpofureP;Gross,KirbyR;Davis,KimberlyA;KurekJr,StanleyJ;Stassen,NicoleA;Patel,MayurB
  • 通讯作者:
    Patel,MayurB
Physiology Considerations in Geriatric Patients.
  • DOI:
    10.1016/j.anclin.2015.05.003
  • 发表时间:
    2015-09-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Alvis, Bret D;Hughes, Christopher G
  • 通讯作者:
    Hughes, Christopher G
The Association of Nonmodifiable Patient Factors on Antipsychotic Medication use in the Intensive Care Unit.
  • DOI:
    10.1177/08850666231198030
  • 发表时间:
    2024-02
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Connell, Jennifer;Mccann, Brittany;Feng, Xiaoke;Shotwell, Matthew S.;Hughes, Christopher G.;Boncyk, Christina S.
  • 通讯作者:
    Boncyk, Christina S.
Acute Management of Traumatic Brain Injury.
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Pratik Pandharipande其他文献

Pratik Pandharipande的其他文献

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{{ truncateString('Pratik Pandharipande', 18)}}的其他基金

Maximizing Efficacy of Goal-Directed Sedation to Reduce Neurological Dysfunction in Mechanically Ventilated Infants and Children Study (mini-MENDS)
在机械通气婴儿和儿童研究中最大限度地提高目标导向镇静效果以减少神经功能障碍 (mini-MENDS)
  • 批准号:
    10685311
  • 财政年份:
    2021
  • 资助金额:
    $ 74.09万
  • 项目类别:
Maximizing Efficacy of Goal-Directed Sedation to Reduce Neurological Dysfunction in Mechanically Ventilated Infants and Children Study (mini-MENDS)
在机械通气婴儿和儿童研究中最大限度地提高目标导向镇静效果以减少神经功能障碍 (mini-MENDS)
  • 批准号:
    10274781
  • 财政年份:
    2021
  • 资助金额:
    $ 74.09万
  • 项目类别:
Altering Sedation Paradigms to Improve Brain Injury and Survival in Severe Sepsis
改变镇静模式以改善严重脓毒症的脑损伤和生存率
  • 批准号:
    8693008
  • 财政年份:
    2012
  • 资助金额:
    $ 74.09万
  • 项目类别:
Altering Sedation Paradigms to Improve Brain Injury and Survival in Severe Sepsis
改变镇静模式以改善严重脓毒症的脑损伤和生存率
  • 批准号:
    8894072
  • 财政年份:
    2012
  • 资助金额:
    $ 74.09万
  • 项目类别:
Altering Sedation Paradigms to Improve Brain Injury and Survival in Severe Sepsis
改变镇静模式以改善严重脓毒症的脑损伤和生存率
  • 批准号:
    9269389
  • 财政年份:
    2012
  • 资助金额:
    $ 74.09万
  • 项目类别:
Altering Sedation Paradigms to Improve Brain Injury and Survival in Severe Sepsis
改变镇静模式以改善严重脓毒症的脑损伤和生存率
  • 批准号:
    8530272
  • 财政年份:
    2012
  • 资助金额:
    $ 74.09万
  • 项目类别:
Altering Sedation Paradigms to Improve Brain Injury and Survival in Severe Sepsis
改变镇静模式以改善严重脓毒症的脑损伤和生存率
  • 批准号:
    8371719
  • 财政年份:
    2012
  • 资助金额:
    $ 74.09万
  • 项目类别:

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