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Professor Marianne Thoresen Physiology and neuroprotection of the newborn Full contact details |
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Projects - Diseases - Processes - Techniques - Equipment - Funding - Collaborations - Teaching - Group members - Publications & further information
Research
Worldwide, newborn infants suffer death or permanent brain damage caused by diseases arising before or around the time of birth. I do translational research aimed at developing effective treatment . By integrating my studies of normal physiological changes in many organ systems with pathological changed seen during disease, I have -together with my students - developed experimental models that mimic global hypoxic-ischemic injury and brain haemorrhage leading to permanent disability in children. The neuroprotective effect of cooling newborns first presented in these models led to clinical trials where we documented the same neuroprotective effect in humans.
Please see FULL CV and PUBLICATIONS for a summary of experimental and clinical projects
I have two main areas of study:
1. Circulation Physiology
Studies include
- cerebral circulation and the influence of blood pressure, temperature and body positioning
- cerebral venous drainage
- positive pressure ventilation
- cardiovascular responses to tilting
- uterine and mammary circulation during normal pregnancy
- skin circulation and thermoregulation
- Physiological Method studies of Doppler velocity, electromagnetic Flowmetry, pletysmography, cerebral circulation, blood pressure and temperature.
- Models of human disease in; newborn asphyxia, intraventricular haemorrhage
2. Neuroprotection
I have developed 3 experimental models mimicking diseases leading to permanent handicap. We use these to understand disease mechanisms and repair processes, and develop treatments for injury caused by asphyxia or low brain blood flow.
Our clinical trials have confirmed effectiveness seen in the experimental models. Now, worldwide, we are applying hypothermia after perinatal asphyxia.
Adding Xenon inhalation to hypothermia doubles neuroprotection in both small and large newborn brain injury models. Our approved Xe delivery system, with safety data and long term survival results, precedes our clinical feasibility study.
Studies include
- Neuroprotection of cooling - cardiovascular effects and effects on regional temperature
- Mechanisms of hypothermic neuroprotection
- EEG during development
- EEG in response to brain injury, temperature, and drugs and pharmacokinetics at normal and low temperature
- Treatment for animals and humans
Details
Our experimental survival model of newborn perinatal asphyxia shows similar pathological changes, neurological signs, EEG changes, multi-organ dysfunction and biochemical changes to those in human infants starved of oxygen or blood flow at birth (hypoxic-ischaemic encephalopathy; HIE).
We were first to experimentally demonstrate the protective effect of hypothermia on the newborn brain after HIE and describe mechanisms of hypothermic neuroprotection, eg lower cerebral excitatory amino acid concentrations and reduced apoptosis. Left untreated, moderate or severe HIE results in 70% of infants dying or having severe disability.
Our hypothermia research has successfully translated into clinical trials. I have funded, planned, carried out and participated in large international trials of hypothermia after perinatal asphyxia that confirm the effectiveness of our experimental studies.
We are now using cooling after HIE as treatment for newborns around the world. I was/am on the advisory board for implementing hypothermia in US, France and Portugal, I am an expert advisor for the National Institute of Clinical Excellence UK, I chair committees of international HT trials and I run teaching courses of clinical hypothermia.
Hypothermia reduces injury by, on average, 35%; we are improving this by developing combination therapy.
Adding xenon to hypothermia increases neuroprotection to 70% in rodents. With our large HIE model we have examined the protective effect of XeHT on brain and organ injury. Since Xe is expensive we've developed a unique delivery system (< 0.2L/h) - low enough for medical use - and plan to translate to the clinic.
In premature infants hydrocephalus following intraventricular haemorrage has no effective treatment. 70% develop cerebral palsy or cognitive delay.
We have developed the first longterm survival neonatal models, and are now testing whether draining out the blood or giving antifibrotic drugs improve reabsorption of cerebrospinal fluid, with the aim of finding a cure.
- The neuroprotective effect of Xenon inhalation and hypothermia in both a small and large neonatal survival model
- Xenon and cerebral blood flow, autoregulation, cerecral pressure reactivity
- The effect of xenon hypothermia on organ protection (heart, lung, liver, kidney)
- Clinical use of Xenon and hypothermia, feasibility study
- Selective head cooling with normothermia as neuroprotection in the premature asphyxiated newborn
- Temperature effects on clinical drugs Mechanisms of hypothermic neuroprotection
- Antifibrotic drugs in the treatment of hydrocephalus after intraventricular haemorrhage
Application of Xenon/hypothermia to adult patient groups like cardiac arrest and stroke. The effect of temperature on normal cardiovascular physiology including drugs.
Ischemic brain damage from many causes and ages; perinatal asphyxia, cardiac arrest, perinatal and adult stroke, cerebral palsy, seizures, cognitive disability,post haemorrhagic ventricular dilatation and subarachnoid haemorrhage
Neuroprotection in a wider sense, white and grey matter injury, cellular markers of brain injury, ATP depletion, excitotoxicity, long term survival, behavioural and neuromotor examinations. The effect of temperature changes on normal and abnormal organ function
Cardiovascular monitoring, laser Doppler flow studies, cardiac echo and cardiac output (invasive and non-invasive), intracranial pressure, regional temperature, EEG, aEEG, neurological assessment, short and long term behavioural testing, ultrasound imaging, biochemistry, immuno-histochemistry, light microscopy
Cardiovascular ('Lidco' invasive cardiac output measurements) and intracranial pressure monitoring equipment (including PRX cerebrovascular reactivity), EEG, temperature, cerebral blood flow velocity (Ultrasound Doppler and Laser Doppler), ultrasound imaging, O2, CO2, and metabolic markers in blood and brain tissue
Projects - Diseases - Processes - Techniques - Equipment - Funding - Collaborations - Teaching - Group members - Publications & further information
Grants and funding
- SPARKS
- Laerdal Foundation for Acute Medicine (Norway)
- Action Medical Research
- BBSRC
- MRC (clinical projects)
- Swedish MRC
Collaborations
In Bristol:
- Professor Seth Love - Neuropathology, Frenchay Hospital
- Professor Elek Molnar - MRC Centre for Synaptic Plasticity, University of Bristol
- Professor Sadeh Suleiman - Bristol Heart Centre, University of Bristol
- Professor Andrew Whitelaw - Neonatology, Southmead Hospital
External collaborators:
External collaborators:
- Professor Linda deVries - Utrecht, The Netherlands
- Professor Donna Ferriero - San Francisco, US
- Professor Pierre Gressens - Paris, France
- Professor Alistair Gunn - Auckland NZ
- Professor Henrik Hagberg - Gothenburg/London
- Dr Mathias Karlsson - Karlstad/Stockholm Sweden
- Helen Porter - Perinatal Pathology, Leicester, UK
- Professor Mary Rutherford - Imperial, London UK
Teaching
Undergraduate and postgraduate teaching in Neonatology Physiology
Running Postgraduate courses x 3/year (CPD approved) - see details of courses for more information.
Publications, recommended reading and further information
Recent selected publications:
Thoresen M, Hobbs C, Wood T, Chakkarapani E, Dingley J.
Cooling combined with immediate or delayed Xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia.
J Cereb Blood Flow Metab 2009 (1-8) E-pub Jan 14
Malcolm R. Battin, Marianne Thoresen, Elizabeth Robinson, Richard A. Polin, A. David Edwards, Alistair Jan Gunn, on behalf of the Cool Cap Trial Group.
Does head cooling with mild systemic hypothermia affect requirement for blood pressure support?
Pediatrics 2009 Mar;123(3):1031-6
Liu X, Borooah M, Stone J, Chakkarapani E, Thoresen M.
The effect of 3-day therapeutic hypothermia on serum gentamicin levels in new born encephalopathic infants.
Pediatrics 2009 (in press)
Chakkarapani E, Thoresen M, Hobbs C, Aquilina K, Liu X, Dingley J.
A closed-circuit neonatal xenon delivery system: technical neuroprotection feasibility study in newborn pigs.
Anesthesia & Analgesia 2009 (in press)
For more general background reading:
Thoresen M, Whitelaw A. (2005)
Therapeutic hypothermia for hypoxic-ischaemic encephalopathy in the newborn infant: review.
Current Opinion in Neurology April 2005;18(2):111-116. (Review)
Erecinsca M, Thoresen M, Silver IA (2003)
Brain metabolism and hypothermia.
Journal of Cerebral Blood Flow and Metabolism 23:513-530
Thoresen M (2000)
Cooling the newborn after asphyxia - physiological and experimental background and its clinical use.
In: Protecting the Perinatal Brain (Ed) Thoresen M - Seminars in Neonatology 5: 61-74
Please also see the article ' Keeping a Cool Head' , on pages 4-5 in the special Neuroscience edition of Re:search, at www.bris.ac.uk/neuroscience/extfiles/re-search_pdf/.
Please also find more about Marianne Thoresen's research and career with her CV .
Projects - Diseases - Processes - Techniques - Equipment - Funding - Collaborations - Teaching - Group members - Publications & further information