Treating Brain Swelling in Pediatric Cerebral Malaria

治疗小儿脑型疟疾引起的脑肿胀

• 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
• 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

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.

脑型疟疾（CM）是指恶性疟原虫感染者发生的原因不明的昏迷 寄生虫血症这种情况很常见，主要影响不到五岁的非洲儿童， 对流行地区的公共卫生产生重大影响。每年675，000例疟疾死亡中的大多数是由CM造成的; 病死率为15%，30%的幸存者在住院时有神经系统异常 放电治疗的主要手段是静脉注射抗疟药物和支持性护理。无干扰 先前已经证明，治疗在降低这种疾病的高死亡率和发病率方面是有效的。 条件我们的长期目标是建立可行的治疗方法，降低这一疾病的死亡率和残疾率。 弱势群体。 我们最近确定，CM儿童的脑容量严重增加与以下因素密切相关： 死亡然而，在幸存者中，脑容量迅速减少，没有具体的治疗。认识到 增加脑容量现在是一个特定的治疗目标，我们将进行一个随机，非盲 两种连续疗法的对照临床试验：高渗盐水或早期机械插管 通风.第一个解决了脑容量增加（细胞毒性水肿）的可能原因，第二个解决了脑容量增加（细胞毒性水肿）的可能原因。 可能的死因（呼吸停止）。我们将对马拉维的CM儿童进行随机分组， 筛查脑MRI（磁共振成像）时脑体积严重增加，为三项研究之一 手臂：常规治疗（床头抬高30度，抗疟药物和支持性治疗） 护理）;常规治疗加静脉高渗盐水;或常规治疗加早期插管， 机械通气我们的主要结果将是孩子被分配的第一次治疗失败 或死亡，以先到者为准次要结局包括出院时的神经功能障碍 以及之后的事我们假设随机分配到一个或两个干预组的受试者将显示出 与随机分组的受试者相比， 常规治疗。 与我们的临床试验同时，我们将评估脑容量增加的候选生物标志物， 儿童CM如果生物标志物显示出识别具有高脑功能的CM儿童的内部有效性， 这将有助于我们的研究结果在非洲医院的MRI不可用。 总之，拟议的研究是重要的，因为我们的干预武器中使用的疗法针对的是一个 CM儿童死亡的重要危险因素。如果任何一个提议的干预措施被证明是 有效，这将是第一次连续治疗已被证明可以减少死亡和/或残疾 在这些孩子中。随着对其他中心的有利干预的广泛采用，公众 这种毁灭性的神经系统感染对健康的影响可能最终会下降。

项目成果

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
• 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
• 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.

Pediatric Cerebral Malaria.

• DOI: 10.1007/s40475-021-00227-4
• 发表时间: 2021-06
• 期刊: Current tropical medicine reports
• 影响因子: 5.4
• 作者: Guenther G;Muller D;Moyo D;Postels D
• 通讯作者: Postels D

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