jamie hutchison - critical care canada · - systemic anti-inflammatory effect. extrapulmonary...
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Inflammation impacting the brain
Jamie Hutchison
CCCF
Toronto, October, 2017
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Outline
• Inflammation in traumatic brain injury and
sub-arrachnoid hemorrhage
• Inflammation in cardiac arrest
• Outline our research program on
inflammation and global cerebral
ischemia/cardiac arrest
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Oligodendrocyte:
Astrocyte:
Basement membrane
Endothelial-selectinSoluble adhesion molecules
Endothelial cell
Molecular Biomarkers
Microglia:CytokinesChemokines
Adherent leukocyte:CytokinesChemokines
Neuron:
Blood-brain barrier
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Thelin EP et. al. Frontiers in Neurology 2017
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Inflammation may be both harmful
and beneficial following brain injury• May lead to breakdown of the blood-brain
barrier, edema and secondary cell death
• May also trigger repair mechanisms
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Cytokine levels are associated
with outcomes in brain injury• Higher levels of acute CSF sVCAM, sICAM-1, and
sFAS as well as IL-7 and IL-8, were associated with
post-traumatic depression at 6 and 12 months post-
TBI. (Juengst SB et al. J Head Trauma Rehabil 2015)
• A high CSF/plasma IL-1β ratio correlated with post-
traumatic epilepsy following brain injury. (Diamond ML
et al. Epilepsia 2015)
• An association between the inflammatory response
following sub-arrachnoid hemorrhage (TNF-receptor 1
and high-sensitivity C-reactive protein) and the
presence of seizures. (Claassen J et al. Ann Neurol
2014)
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The cytokine response in ECF in the treated group resembled that
of the classical pro-inflammatory microglial activation (M1), with
increased IL-1β and low levels of IL-4 and IL-10. These findings
were counterintutitive given the classification of IL1ra as an “anti-
inflammatory cytokine.”
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Types of studies needed of
inflammation in TBI and SAH
• Using arrays of cytokines from plasma,
CSF and microdialysis – specialized
centres
• Principal component analysis
• Combined with neuroimaging studies (e.g.
Pet)
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Inflammation in cardiac arrest
• Following cardiac arrest there is a
systemic inflammatory response syndrome
characterized by release of suppressive
cytokines (i.e., interleukin IL-1, IL-2, IL-3,
IL-6, TNF-α)
• Contributes to suppression of pituitary-
adrenal axis
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Mentzelopoulos et. al. JAMA 2013
• 3 Greek centres, in-hospital cardiac arrest
• N=268 adults
• RCT to epinephrine, vasopression and
methylprednisolone vs epinephrine
• Post-resuscitation shock – hydrocortisone
vs placebo
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Metzelopoulos, et. al.
JAMA 2013
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Theoretical paradigm
Inhaled Nitric Oxide
_
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Our Rodent 2 Vessel Occlusion
(VO) Model• Male C57Bl/6 mouse, 20-25g
• 10 minutes of bilateral carotid artery occlusion
Dermot Doherty and John Sled
Jeffrey Shih
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Interleukin (IL)-1β is expressed in neurons at 24
hours following 2VO ischemia
Hippocampus (CA1)
IL-1β Neuronal - N Merged
Ryan Salewski, MSc, Institute for Medical Science, University of Toronto
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Hutchison et al. in submission
2 hours post
cerebral ischemia
4h Hypothermia
C
Ryan Salewski, MSc thesis
Hypothermia therapy reduces leukocyte
adhesion post global cerebral ischemia (GCI)
in mice
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Hypothermia reduces microglia activation post GCI
in mice (72 hours)
Nguyen. MSc. thesis
Cell
count
Cell
count
LP
SH
T-2
VO
NT
-2V
OH
T-s
ham
NT
-sham
CortexDGCA-3CA-2CA-1
NT-2VO HT-2VO
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Anti-CD18 ab therapy is neuroprotective post GCI in mice
Salewski et al. in submission
4 weeks post surgery
24 hours post IL-1β injection
Ryan Salewski and Dermot Doherty
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• Mice serum from GCI study (N=10 per group)
1) Sham, 2) 2VO+anti-CD18 ab, 3) 2VO+control
ab
- Found 400 proteins with Mass Spectrometry
- Kallikrein as a potential biomarker?
Proteomics of mouse serum 24 hours post GCI (Sugiura, Salewski, Taylor)
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Kallikrein
Kallikrein gene delivery
- enhances NO formation
- decreases oxidative stress
- activates cell surviving signaling pathways
Vasoactive kininLMW kininogen
Kinin B2 receptor
kallikrein
+
(plasma, peripheral tissues)
NO-cGMP Prostacyclin-cAMP
Modulate broad
spectrum of
cellular functions
Kallikrein, through the endogenous kinin B2 receptor, plays a crucial role in
protection against focal cerebral ischemia in mice (Xia et al. Hypertension 2006)
Tissue kallikrein-kinin system exert protective effects in ischemic heart injury
(Yoshida et al. Hypertension 2000, Yin J Biol Chem 2005)
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Rationale for iNO instead of
anti-CD18• Trial of anti-CD18 in humans with stroke
showed harm
• iNO inhibits neutrophil adhesion in remote
ischemic vascular beds and is likely safe
in humans
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Background 1“Global Cerebral Ischemia (GCI) during
cardiac arrest leads to a devastating
neurological injury
Return of spontaneous circulation rate has
improved dramatically but neurological outcome
has not improved (Bobrow BJ et al. JAMA 2008, Rea TD et al. Circulation 2006)
Sudden cardiac arrest 50-100/100,000
population
Out-of-hospital cardiac arrest survival rate is
4.6% in North America(Fishman GI, et al. Circulation 2010)
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Background 2Adult cardiac arrest => Therapeutic
hypothermia or temperature
managementThe Hypothermia after Cardiac Arrest Study Group. NEJM 2002,
Bernard SA et al. NEJM 2002
Nielson N et al. NEJM 2013
Multiple papers in neonates with HIE but less neuroprotective in
children (Moler et al. NEJM X 2)
• inhaled Nitric Oxide (iNO) ?
- Pulmonary hypertension
- Acute oxygenation failure
“selective pulmonary vasodilator”
- Systemic anti-inflammatory effect
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Extrapulmonary effects of iNO
Organ Effect of iNO Species
CNS ↑Cerebral blood flow Swine
CSF [Nox] ↑ proportionally with ↑iNO dose Swine
Alters EEG Human
↑Neurodevelopmental outcome in premature infants Human
Bowel↓Leukocyte adhesion in microcirculation during
sepsis and ischemia-reperfusionRat, cat
↑Mesenteric blood flow after ischemia-reperfusion Cat
Immune
systemPMN respiratory burst attenuated Human
↓Pulmonary PMN sequestration during ECMO Swine
↓Platelet-leukocyte interactions in ARDS Human
McMahon et al. Proc Am Thorac Soc 2006
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iNO and brain
Ischemic brain injury• In the mouse cardiac arrest model, iNO improves survival rate,
neurological and LV function, reduces inflammatory cytokine induction.
(Minamishima et al. Circulation 2011)
• In stroke mouse and rat, iNO prevents ischemic brain damage by
dilating the collateral arteries.
(Terpolilli et al. Circulation research 2012)
(Charriaut-Marlangue et al. Stroke 2012)
Cerebral Malaria• In CM mouse model, iNO in addition to artesunate reduces systemic
inflammation and endothelial activation significantly, preserves brain vascular integrity, and improves mortality
(Serghides et al. PloS1 2011)
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NO in the human respiratory cycle
McMahon et al. Proc Am Thorac Soc 2006
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Proposed parallel studies of iNO in global cerebral
ischemia in mice and cardiac arrest in children and
adults
Sham 2VO
forebrain
hindbrain
no
perfusion
Peripheral
Blood
Proteomics
Neurological
Functional
Outcomes
Death –
Brain Molecular
Expression and
Cell Death
Time
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Hypothesis
iNO therapy is neuroprotective post
GCI in mice
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Our research questions
<Rodent model>
• Is iNO therapy neuroprotective post GCI?
• Are there useful serum biomarkers associated with the neuroprotection of iNO post GCI?
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Experimental paradigm
1.
Ischemia / Sham surgery
10 minutes
iNO 40 ppm for 48 hrs
for treatment group
Peripheral blood
proteomics
Neurological
functional outcomes
Death- brain
molecular expression
and cell death
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Experimental series
• Post ischemic neuroprotection
iNO vs placebo
1) 2VO + iNO 40 ppm for 48 hours
2) 2VO + placebo gas 48 hours
3) Sham + iNO 40 ppm for 48 hours
Group 1 serum biobanked at 48 hours
Group 2 Neurological outcomes then brains
removed at 5 days for FluoroJade B
staining (cell death) and immunostaining
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Cardiac
Arrest
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Inhaled Nitric Oxide During In-
Hospital Cardiac Arrest.
• Phase I
• Determine optimum delivery system
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Phase II
Unblinded study in adults and children. ? gas
Primary questions
• Can iNO be delivered during CPR?– Patient identification
– Recruitment
– Timing of administration
– Blinding of study gas
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Phase IIIPlacebo controlled study in adults and children
Primary questions
• Can patients be identified and randomized?
• Can the study gas be administered and concealed during CPR?
Secondary questions
• Patient outcomes– Serum proteomics (same as mouse protocol)
– ROSC
– Survival
– LOS
– Neurological outcomes
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iNO in Cardiac Arrest
R
Eligibility:
- in hospital cardiac arrest of 5 minutes duration
iNO 40 ppm (48 h.)
Inhaled placebo gas (48 h.)
•N = ?20 children and adults
•Masked follow-up 3 and 6 months
- Glasgow Outcome Scale
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Phase IV
RCT of iNO vs placebo gas during in-hospital cardiac arrest
Multicenter RCT
Primary and secondary outcomes
• Survival
• Neurological recovery
• ROSC
• Neuroprotective serum biomarker discovered in rodent and human pilot RCT
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Summary
• Inflammation is a double edged sword
following TBI and SAH
– More mechanistic studies are needed to
determine the role of inflammation and in which
subgroups of patients anti-inflammatory therapies
hold promise
• Inflammation may also impact the brain
following cardiac arrest
– iNO holds promise as an anti-inflammatory
neuroprotective therapy following cardiac arrest
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AcknowledgementsLaboratory:
– Technicians:• Rachel Shaye
– Graduate students and post-Docs:
• Dermot Doherty, Ryan Salewski, Jeffrey Shih, Anh Nguyen, Asumi
Sugiura
– Collaborators:• Cynthia Hawkins, Sheena Josselyn, Paul Frankland, Paul Taylor, Alison
Fox-Robichaud
Clinical:
- John Granton, Laurie Morrison, Damon Scales, Vinay Nadkarni