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Principal Investigator: Daniel S Chertow
Organization: CLINICAL CENTER
Fiscal Year: 2019
Funding agency: NIH Clinical Center
Project 1: In this study, we will expose pregnant rhesus macaques to ZIKV in the first, second, or third trimesters of their 165-day gestational period. Following exposure, we will investigate fetal brain development and evolution of brain injury using serial fetal brain imaging (MRI and ultrasound), and monitor the appearance of a maternal serum marker of fetal brain injury. We will also sample the amniotic fluid to assess viral replication. Postnatally, we will humanely euthanize one newborn/dam pair from each cohort for detailed viral pathologic studies. We will then longitudinally observe the surviving infants for neurological abnormalities and the persistence of viremia. We will infect both infants born to ZIKV-infected mothers after passive immunity wanes and aged-matched control animals born to uninfected mothers.
This manuscript in nearing submission.
Project 2: We developed a supportive critical care model in 5 Kg Indian Origin Rhesus Macaques under biosafety level (BSL) 2 conditions. In this model, animals are provided care and physiologic monitoring similar to that provided to humans in the intensive care unit. Animals are deeply sedated, placed on mechanical ventilation, and closely monitored by trained bedside technicians. In this setting fluid status, serum electrolyte and glucose levels, and acid-base status can be frequently monitored and closely adjusted. Similarly, this model allows for titration of continuous infusion of multiple vasopressors to maintain blood pressure and frequent dosing of medications such as empiric antibiotics and stress-dose steroids which are standard of care in humans with vasopressor-refractory shock. This level of care cannot be provided to awake animals with tethered indwelling vascular catheters.
Measurement of physiologic parameters including cardiac output and pulmonary artery occlusion pressure (PAOP) allows one to differentiate between the 4 categories of shock (i.e., hypovolemic, cardiogenic, obstructive, and distributive), which is essential to optimizing clinical management of severe infections. The contribution of the different categories of shock to EVD pathophysiology remains incompletely characterized. The pulmonary artery (PA) catheter utilized in this model remains the gold standard for assessing volume status and physiology of shock in humans. Specifically, the PA catheter provides a direct measure of cardiac output and an estimate of ventricular pre-load (intravascular volume status) and peripheral vascular resistance (determination of peripheral vasodilation), which can be intermittently assessed at the bedside to guide blood pressure management with titration of intravenous fluids and vasopressors. The PA catheter has been safely implemented in this model and provides reliable physiologic data consistent with those observed in humans.
A manuscript describing the ICU model absent infection is nearing submission. The first round of bacterial sepsis studies has been completed and is in a data-analysis phase. Transition of the ICU model into BSL-4 has been approved and is in the early implementation stage.
Terms: <0-4 weeks old><1st trimester><2nd trimester><3rd trimester><Acids><Acquired brain injury><Amniotic Fluid><Animal Model><Animal Models and Related Studies><Animals><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Appearance><Approaches to prevention><Aqua Amnii><Arterial Obstruction><Arterial Occlusion><Artery Obstruction><BP control><BP homeostasis><BP management><BP regulation><Blood Pressure><Blood Serum><Blood Vessels><Brain><Brain Injuries><Brain Nervous System><Brain imaging><CNS Nervous System><Cardiac Output><Caring><Categories><Catheters><Cells Placenta-Tissue><Central Nervous System><Circulatory Collapse><Clinical><Clinical Management><Congenital neurologic anomalies><Consumption Coagulopathy><Continuous Infusion><Control Animal><Counseling><Critical Care><Critical Illness><Critically Ill><D-Glucose><Data><Data Analyses><Data Analysis><Development><Dextrose><Diagnosis><Diagnostic><Disease><Disease Outbreaks><Disorder><Disseminated Intravascular Coagulation><Dose><Drugs><Dysfunction><EBOV><Early Placental Phase><Ebola><Ebola Hemorrhagic Fever><Ebola Virus Disease><Ebola virus><Echography><Echotomography><Electrolytes><Encephalon><Evolution><Exhibits><Experimental Therapies><Failure><Fetus><First Pregnancy Trimester><First Trimester><Functional disorder><Genetic><Gestation><Glucose><Goals><Gold><Human><Hypovolemics><IV Fluid><Image><Immune response><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Individual><Infant><Infection><Intensive Care Units><Intravenous Fluid><Investigation><Investigational Therapies><Investigational Treatments><Last Trimester><Life><Light><Liquid substance><Liquor Amnii><MR Imaging><MR Tomography><MRI><Macaca><Macaca mulatta><Macaque><Magnetic Resonance Imaging><Manuscripts><Measurement><Measures><Mechanical ventilation><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medical Ultrasound><Medication><Microcephaly><Midtrimester><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular><Monitor><Monkeys><Mothers><NMR Imaging><NMR Tomography><Nervous System Abnormalities><Nervous System Anomalies><Nervous System Congenital Abnormalities><Nervous System Congenital Anomalies><Nervous System Congenital Malformations><Nervous System Injuries><Nervous System Malformations><Nervous System Trauma><Nervous System damage><Neuraxis><Neurologic><Neurological><Neurological Damage><Neurological Injury><Neurological trauma><Newborn Infant><Newborns><Normal Placentoma><Nuclear Magnetic Resonance Imaging><Observation research><Observation study><Observational Study><Observational research><Outbreaks><Passive Immunity><Pathogenesis><Pathologic><Peripheral><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Photoradiation><Physiologic><Physiologic Monitoring><Physiological><Physiological Monitoring><Physiology><Physiopathology><Placenta><Placenta Embryonic Tissue><Placental Development><Placentation><Placentome><Pregnancy><Preventative treatment><Prevention approach><Preventive treatment><Pulmonary Artery><Pulmonary artery structure><Refractory><Reproduction><Research><Rhesus><Rhesus Macaque><Rhesus Monkey><Sampling><Savings><Second Pregnancy Trimester><Second Trimester><Sepsis><Serum><Shock><Steroid Compound><Steroids><Stress><Supportive Therapy><Supportive care><Third Pregnancy Trimester><Third Trimester><Titrations><Training><Treatment Protocols><Treatment Regimen><Treatment Schedule><Ultrasonic Imaging><Ultrasonogram><Ultrasonography><Ultrasound Diagnosis><Ultrasound Medical Imaging><Ultrasound Test><Vascular resistance><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasodilatation><Vasodilation><Vasopressor Agents><Vasorelaxation><Ventricular><Viral><Viral Diseases><Viremia><Virus Diseases><Virus Replication><ZIKA><ZIKV><ZIKV infection><Zeugmatography><Zika Virus><Zika virus infection><aged><artery occlusion><awake><base><blood infection><blood pressure control><blood pressure homeostasis><blood pressure management><blood pressure regulation><bloodstream infection><brain damage><brain visualization><brain-injured><circulatory shock><cohort><congenital nervous system disorder><data interpretation><design><designing><developmental><diagnostic ultrasound><drug/agent><early biomarkers><early detection biomarkers><early detection markers><ebolavirus><experimental therapeutic agents><experimental therapeutics><fetal><fetal brain injury><fluid><heart output><host response><human model><imaging><immunoresponse><improved><liquid><maternal serum><maternal serum markers><mechanical respiratory assist><micrencephaly><microencephaly><model of animal><model organism><mortality><neurotrauma><newborn child><newborn children><non-human primate><nonhuman primate><pathogen><pathophysiology><postnatal><pregnant><pressure><prognostic power><prognostic utility><prognostic value><regulate BP><regulate blood pressure><sonogram><sonography><sound measurement><standard of care><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><ultrasound><ultrasound imaging><ultrasound scanning><vascular><vasopressor><viraemia><viral infection><viral multiplication><viral replication><viral sepsis><virus infection><virus multiplication><virus-induced disease><virusemia><zika infection><zika viral infection><zikav>