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Neonatal hypoxia Ischemia Flashcards

1
Q

What is Neonatal hypoxia ischaemia?

A

most common cause of death and disability in human neonates, and is often associated with persistent motor, sensory, and cognitive impairment

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2
Q

What causes hypoxic ischemic brain injury?

A
  1. Maternal factors
  2. Cord factors
  3. Placemtal factors
  4. Uterine factors
  5. Neonatal postnatal events such as shock, respiratory or cardiac arrest
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3
Q

What are factors which influence damage?

A
  1. Etiology
  2. Degree and duration of hypoxia ischaemia
  3. Maturational stage of brain
  4. Regional changes in cerebral blood flow
  5. General health of the infant prior to injury
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4
Q

What is Neonatal encephalopathy (NE)?

A

Descriptive term for clinical constellation of neurological dysfunction

  1. Difficulty with initiating and maintaining respiration
  2. Depression of tone and reflexes
  3. Subnormal level of consciousness
  4. Seizures
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5
Q

What is a specific terminology related to hypoxic ischemic injury?

A

Hypoxic Ischemic Encephalopathy (HIE)

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6
Q

What is Neonatal encephalopathy?

A
  1. Major cause of global mortality
  2. 4 million children die each year - 1/4th from HI injury
  3. 85% in SE asia & SS Africa
  4. One of the highest numbers of DALY’s
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7
Q

What is the incidence of neonatal encephalopathy?

A

15-20/1000 (SS Africa)
1-3/1000 in high income countries

1/4th from HI injury

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8
Q

What is the outcome following perinatal HI at term?

A
  1. 10-15% of affected infants die in the first few days [studies come from developed countries]
  2. 15% of survivors develop cerebral palsy [motor problems, one or both side weakness]
  3. 40% of survivors, other significant problems:
    - Deafness
    - Blindness
    - Epilepsy
    - Global developmental delay [cognitive problems]
    - Autism
    - Problems with cognition, memory and fine motor skills
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9
Q

Mortality in children < 5 years

[WHO]

A
  1. 2.6 million deaths, ~46% of all < 5 deaths, occurred during neonatal period
  2. ~7000 newborn death everyday
  3. Majority of neonatal deaths are on first day [relative to HI]
  4. ~1 million die on first day
    other 1 million die within the next 6 days
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10
Q

What does mitochondria help to produce?

A

NADH
Which goes into the ETC
produce energy in the form of ATP

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11
Q

What can MRS help to identify?

A

The concentration of different chemicals in the brain

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12
Q

Phosphorus Magnetic Resonance spectroscopy (neonatal - preclinical work)

A

Direct information about the energy

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13
Q

Proton magnetic resonance

A

Direct information about the brain lactate

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14
Q

Broadband NIRS

A

Information about what is happening in the ETC

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15
Q

What are some examples of metabolites of the 1H MRS?

A
  1. Choline
  2. Creatine
  3. NAA
  4. Lactate
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16
Q

Choline

A

Cell membrane

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17
Q

Creatine

A

Energetics

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18
Q

NAA

A

Marker of neuronal/axonal density and viability

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19
Q

Lactate

A

Marker of failed oxidative phosphorylation

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20
Q

What can be used for biomarker?

A
  1. NAA

2. Lactate

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21
Q

What are the phases of brain injury following HI?

A
  1. Primary phase (mins)
  2. Latent phase (hours)
  3. Secondary phase (days)
  4. Testing phase (weeks, years)
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22
Q

What is primary phase?

A

Cerebral hypoxia

Ischemia of sufficient severity to deplete tissue energy reserves

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23
Q

What is the latent phase?

A

Repurfusion and re-oxygenation + restoration of glucose use and high energy phosphates

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24
Q

What is secondary phase?

A

Decrease in high energy phosphate in parallel with cell injury

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25
What is testing phase?
Long term cell regeneration and repair
26
What are the key milestone leading to Therapeutic Hypothermia as routine therapy
1. Piglet model
27
What is the piglet model
1. Hypothermia ameliorates brain energy decline on MRS 2. 1997 - Gunn colleagues show that 75% hypothermia is safe and effective in reducing cytotoxic oedema 3. 2005 - cooling reduces mortality without increasing disability in survivors of perinatal hypoxia ischaemia 4. 2012- NICE- therapeutic hypothermia become standard treatment of moderate to severe neonatal encephalopathy
28
What are the effect of cooling on conventional brain MRI?
Cooled infants more likely to have normal scans
29
What did cooling reduce the incidence of lesions in?
1. Basal Ganglia 2. White matter 3. Abnormal posterior limb of internal capsule
30
What is insult severity associated with?
Shortening of the subsequent latent-phase, worse secondary energy failure and more severe cortical damage
31
How do we assess injury?
1. alpha EEG/EEG 2. CRUSS 3. MRI/1H MRS Future modalities 4. Broadband NIRS 5. 31P MRS
32
What is alpha EEG/EEG?
The most promising test: amplitude integrated electroencephalography sensitivity and specifity
33
What does cooling alter?
Predictive value of alpha EEG
34
What is the most quantitiative MR biomarker for predicting neurodevelopmental outcome after NE?
Deep grey matter Lac/NAA | -Lac/NAA < 0.3 indicates good outcome
35
Near Infrared Spectroscopy
Information regarding cerebral heamodynamics and oxygenation
36
What did Barkovich and others describe for injury on conventional MRI?
1. Watershed (white matter loss at the boundaries of territories of 3 major cerebral arteries) 2. Basal Ganglia and thalamic lesions 3. Total cortical loss
37
What is the sudden profound hypoxia ischaemia?
1. placenta separates from uterine wall 2. Blood pressure falls 3. Decrease in oxygenated blood supply to fetus via umbilical cord 4. Blood oxygenation concentration falls
38
What is the cool aid trial?
Large, multicentre trial, international trial | - glucose control is not optimal , chance of injury increases
39
What happens if the baby has no facility to get cooling treatment?
The baby has to be stabilised | and picked up by transport team
40
Time to start treatment from the incidence
Important factor for the outcome
41
What is intrapartum?
What happens around the time of the birth
42
What is the risk determined by?
Where you are born
43
How many births are in the high income group?
11 million births | They have full intensive care
44
How many births are in the middle income group?
34 million births | There are some unit intensive care and some degree of support
45
What does low income have?
Facility birth | 40m
46
In what group are there more home birth?
Low income group | highest: 50 million birth
47
What do the survivors have?
Significant neurodevelopmental disability | Significant burden to family and society and country
48
What happened in 1 in 4 deaths?
Problems with adequate staffing and resources
49
What do we need to produce energy?
Glucose
50
What is the process of cerebral metabolism?
1. Glucose goes through the glycolysis 2. If oxygen present, pyruvate goes to Acetyl-coA and goes into Kreb's cycle and produces NADH and a little of FADH which is transferred to ETC which produces ATP 3. In the absence of oxygen, lactate is produced and little bit of energy
51
How can you monitor the brain?
1. proton magnetic resonance sprectoscopy 2. Electron transport chain - there are 4 different complexes from lungs - when electron flows through cytochrome oxidase - there is a chain of reaction -broadband near spectroscopy
52
How can you confirm the energy state of the brain?
phosphorus magnetic resonance spectroscopy and identify it | - Gives background and main understanding of pathogenic mechanism of this condition
53
What does PCr tell you?
The energy of the brain
54
What is lactate by NA?
The most sensitive and specific biomarker used clinically
55
What happens in severe injury?
Latent phase is small | Goes to secondary energy failure
56
What does cooling treatment help?
Can prevent secondary energy failure | Biggest culprit which causes brain damage
57
What is cooling?
Neurprotective therapy
58
Therapeutic hypothermia in clinical practice
1. Connect baby to several controlled machine 2. Temperature on the machine: 33.5 3. Bring the temperature by 3.5 points 37-3.5=33.5 4. Maintain that over 72 hours 5. Gradually warm it over 14 hours 6. Take baby to MRI to see the extent of damage
59
What responds to cooling treatment?
moderate-to-severe encephalopathy
60
How can you prevent 1 death of disability?
NNT 6 babies=moderate encephalopathy | NNT 7 babes = severe
61
How many adults need to take a statin to prevent 1 cardiac arrest?
Around 8-100
62
Why is deep grey matter important?
Area of highest metabolic rate in the brain
63
Why is the temperature 33.5 hours and why is the temperature 72?
look at brain structures after deeper cooling and see what happens without cooling = pretty much the same it has the best outcome
64
What is the standard assessment for injury?
1. electrical lead on the head and monitor with EEG
65
What is alpha EEG/EEG?
Semi-logarithmic compressed version of EEG small period - see larger duration of the study and quickly identify if there is a problem - very sensitive and specific before the start of the cooling
66
What is normal for aEEG?
Amplitude integrated EEG | Thinning and thickening of the amplitude integrated bands
67
What does lactate nA have?
100% sensitivity | about 97% specifity to predict motor outcome
68
What are the biomarkers after therapeutic hypothermia following HI?
1. Motor outcome 2. Cognitive outcome 3. Language outcome
69
What is near infrared spectroscopy?
Information regarding cerebral haemodynamics and oxygenation
70
Watershed injury
White matter looks bright
71
What is the watershed predominant pattern?
1. Parasagittal | 2. Borderzone
72
What are the watershed predominant pattern characterstics
Lesion of the cerebral cortex and subcortical white matter with a characteristic distribution over the superomedial aspects of the cerebral convexities Necrosis of the cortex and the immediately adjacent white matter, affecting mainly parieto-occipital regions
73
What are acute total hypoxia ischaemia?
Basal Ganglia and Thalamus uterine rupture, cord prolapse, placental abruption Infants usually require major resuscitation Apgar score < 5 at 5 mins Associated with Cerebral Palsy preserved intelligence if focal quadriplegic CP if widespread
74
What is partial prolonged asphyxia
WatershedInfants usually do not require major resuscitation at birth Apgar scores > 5 at 5 mins Extensive white matter involvement predicts cognitive deficits
75
What are the therapeutic agent | Adjunct therapy with cooling?
1. Noble gasses 2. Xenon 3. Argon 4. Melatonin 5. Remote ischaemic post conditioning 6. Stem cell therapies 7. Epo 8. Allopurinol (Albino studies)
76
Noble gases
One clinical trial completed | Pre-clinical studies completed
77
Melatonin
New formulation | Pre-clinical studies – promising result
78
Remote ischaemic post conditioning
Pre-clinical studies completed | Further studies with cooling/therapeutic wind
79
Stem cell therapies
Pre-clinical studies and clinical trials
80
EPO
Phase 1 study | Phase 2 study starting in the US
81
Allopurinol (albino study)
Horizon 2020 study. 14 European centres 2016-2020

C2 Modules CLINICAL (26 decks)

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