Treating Brain Swelling in Pediatric Cerebral Malaria

治疗小儿脑型疟疾引起的脑肿胀

基本信息

批准号：
10539346
负责人：
Terrie Ellen Taylor
金额：
$ 56.42万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-12 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10539346
关键词：
5 year old Address Admission activity Adoption Affect African Antimalarials Area Autopsy Beds Biological Markers Blood Vessels Brain Edema Caring Case Fatality Rates Cause of Death Cerebral Malaria Cessation of life Child Childhood Clinical Clinical Trials Coma Controlled Clinical Trials Data Death Rate Edema Ensure Erythrocytes Etiology Failure Fluorescein Angiography Future Goals Head Hospitals Hour Human Resources Hyperemia Infection Infusion procedures Intensive Care Intervention Intravenous Intubation Life Magnetic Resonance Imaging Malaria Mechanical ventilation Medical Morbidity - disease rate Nervous System Trauma Neurologic Parasitemia Parasites Parental Consent Pathogenesis Patients Pediatric Neurology Plasma Plasmodium falciparum Population Positioning Attribute Public Health Randomized Research Resources Retina Risk Risk Factors Saline Supportive care Survivors Syndrome Time Training Tropical Medicine Urine Visit Vulnerable Populations biobank brain magnetic resonance imaging brain volume candidate marker cerebral microvasculature clinical biomarkers cytotoxic design disability efficacious intervention falls high risk in vivo intervention effect malaria infection mortality mortality risk potential biomarker primary outcome randomized, clinical trials rate of change respiratory scale up screening secondary outcome standard of care therapeutic target three-arm study treatment arm uptake

项目摘要

Cerebral malaria (CM) is defined as an otherwise unexplained coma in a patient with Plasmodium falciparum parasitemia. The condition is common, primarily affects African children less than five years old, and has a large public health impact in endemic areas. Most of the 675,000 malaria deaths each year are from CM; the case fatality rate is 15%, and 30% of survivors have neurological abnormalities at the time of hospital discharge. The mainstay of treatment is intravenous antimalarial drugs and supportive care. No adjunctive therapy has previously been proven effective in decreasing the high rates of mortality and morbidity in this condition. Our long-term goal is to establish feasible therapies that decrease death and disability rates in this vulnerable population. We recently determined that severely increased brain volume in children with CM is strongly associated with death. In survivors, however, brain volumes diminished quickly, without specific treatment. Recognizing that increased brain volume is now a specific therapeutic target, we will perform a randomized, non-blinded controlled clinical trial of two adjunctive therapies: hypertonic saline or early intubation with mechanical ventilation. The first addresses a likely cause of increased brain volume (cytotoxic edema) and the second addresses the likely cause of death (respiratory arrest). We will randomize Malawian children with CM and severely increased brain volumes on screening brain MRI (magnetic resonance imaging) to one of three study arms: usual treatment (elevation of the head of the bed by 30 degrees, antimalarial drugs, and supportive care); usual treatment plus intravenous hypertonic saline; or usual treatment plus early intubation and mechanical ventilation. Our primary outcome will be failure of the first treatment to which the child is assigned or death, whichever comes first. Secondary outcomes include neurological disabilities at hospital discharge and thereafter. We hypothesize that subjects randomized to one or both of our intervention arms will show significantly decreased mortality without a rise in neurological morbidity, compared to those randomized to usual treatment. Simultaneously with our clinical trial, we will evaluate candidate biomarkers of increased brain volume in children with CM. If a biomarker shows internal validity for identifying children with CM with high brain volumes, this will facilitate uptake of our study results into African hospitals where MRI is unavailable. In summary, the proposed research is significant because the therapies used in our intervention arms target an important risk factor for death in children with CM. Should either of the proposed interventions prove to be efficacious, it will be the first time an adjunctive therapy has been shown to decrease death and/or disability rates in these children. With widespread adoption of a favorable intervention into other centers, the public health impact of this devastating neurological infection may finally fall.

脑疟疾（CM）定义为恶性疟原虫患者的原本无法解释的昏迷寄生虫。这种情况很常见，主要影响不到五岁的非洲儿童，并且有一个公共卫生在地方性地区的影响很大。每年675,000人死亡中的大多数来自CM；这病例死亡率为15％，30％的幸存者在医院时患有神经异常释放。治疗的主要需要是静脉内抗疟药和支持性护理。没有辅助以前已证明治疗可有效降低高死亡率和发病率健康）状况。我们的长期目标是建立可行的疗法，以降低此处的死亡和残疾率脆弱的人口。我们最近确定CM儿童的大脑体积严重增加与死亡。然而，在幸存者中，脑量迅速减少，没有特定的治疗方法。认识到这一点大脑体积增加是一个特定的治疗靶标，我们将执行一个随机的，非盲的靶标两种辅助疗法的对照临床试验：高渗盐水或机械插管通风。第一个解决了可能导致大脑体积增加（细胞毒性水肿）和第二个原因解决可能的死亡原因（呼吸逮捕）。我们将随机将马拉维儿童带有CM和在筛选脑MRI（磁共振成像）上严重增加了大脑体积为三项研究之一武器：通常的治疗关心）;通常的治疗以及静脉注射高渗盐水；或通常的治疗以及早期插管和机械通气。我们的主要结果将是未分配孩子的第一种治疗方法或死亡，以先到者为准。次要结果包括医院出院时神经残疾此后。我们假设主体随机与我们的一个或两个干预臂一起显示与随机分配给神经系统发病率的死亡率显着降低而没有增加通常的治疗。同时，在我们的临床试验中，我们将评估候选生物标志物的大脑体积增加 CM的孩子。如果生物标志物显示出内部有效性，以识别大脑高的CM儿童数量，这将有助于我们对MRI不可用的非洲医院的吸收。总而言之，拟议的研究很重要，因为我们干预臂中使用的疗法针对 CM儿童死亡的重要危险因素。提议的干预措施是否应被证明是有效的是，这将是首次证明辅助疗法可减少死亡和/或残疾这些孩子的比率。随着广泛采用有利的干预措施，公众这种毁灭性神经感染的健康影响可能最终会下降。

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）

How to Push the Limit: Developing Informed Research and Implementation Programs in Resource-Limited Settings.

如何突破极限：在资源有限的环境中制定知情研究和实施计划。

DOI：
10.1097/pcc.0000000000001565
发表时间：
2018
期刊：
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
影响因子：
0
作者：
Muttalib,Fiona;Doctor,Allan
通讯作者：
Doctor,Allan

Multiple Organ Dysfunction Syndrome and Pediatric Logistic Organ Dysfunction-2 Score in Pediatric Cerebral Malaria.

DOI：
10.4269/ajtmh.22-0140
发表时间：
2022-10-12
期刊：
The American journal of tropical medicine and hygiene
影响因子：
0
作者：
Johnson H;Raees M;Urbina E;Muszynski J;Seydel K;Taylor T;O'Brien N
通讯作者：
O'Brien N

Mechanisms of Transcranial Doppler Ultrasound phenotypes in paediatric cerebral malaria remain elusive.

DOI：
10.1186/s12936-022-04163-0
发表时间：
2022-06-21
期刊：
MALARIA JOURNAL
影响因子：
3
作者：
O'Brien, Nicole F.;Fonseca, Yudy;Johnson, Hunter C.;Postels, Douglas;Birbeck, Gretchen L.;Chimalizeni, Yamikani;Seydel, Karl B.;Gushu, Montfort Bernard;Phiri, Tusekile;June, Sylvester;Chetcuti, Karen;Vidal, Lorenna;Goyal, Manu S.;Taylor, Terrie E.
通讯作者：
Taylor, Terrie E.

Cerebral malaria: insight into pathology from optical coherence tomography.

DOI：
10.1038/s41598-021-94495-9
发表时间：
2021-08-03
期刊：
Scientific reports
影响因子：
4.6
作者：
Tu Z;Gormley J;Sheth V;Seydel KB;Taylor T;Beare N;Barrera V;Proudlock FA;Manda C;Harding S;Gottlob I
通讯作者：
Gottlob I

Pediatric Cerebral Malaria.