1. Cerebral Deoxyhemoglobin Imaging
A biomarker for poor neurological outcomes in neonates who suffered hypoxic ischemic brain injury
Austin Trinh MD, Brenda Bartnik-Olson PhD, Matthew Phelps BS, Daniel Kido MD, Paul Jacobson MD, Paggie Kim MD

2. Hypothesis 1.
Absent and extremely prominent cerebral veins on SWI are associated with poor neurological outcomes in neonates who suffered hypoxic ischemic brain injury (HI-BI)
Absent and extremely prominent cerebral veins on SWI are associated with poor neurological outcomes in neonates who suffered HI-BI

3. Secondary Aims 2.
Does hypothermia therapy have an affect on this relationship?
Do the cerebral venous appearances differ between the hypothermia and nonhypothermia patients?

4. Background 1-2 neonates per 1000 live births
High mortality and morbidity rate
Approximately 1-2 neonates per 1000 live births suffer from HIBI each year in the United States, with intra-uterine asphyxia being the major cause. Neonates who survived from HI-BI often have long-term disabilities, and they make up of 20% of cerebral palsy patients.
Research studies suggest that HI-BI is caused by cascade of molecular events that lead to necrosis and apoptosis of brain cells from hypoxia.. Animal models of HI-BI show that there is a “window of opportunity” when brain cells that are committed to die can be rescued.
Currently, it was thought that whole-body hypothermia therapy can rescue these cells and prevent delayed cell death during this “window of opportunity. However, there are very limited therapeutic options for HI-BI, largely due to limited availability of surrogate makers.
As such, we believe that SWI can potentially be a surrogate maker that might help to guide management for whole-body hypothermia therapy or other potential future therapies.

5. SWI
Studies have shown that increased levels of deoxygenated blood is seen with HI-BI Sequence is particularly sensitive at detecting extravascular blood products and deoxygenated blood
Conventional MRI itself plays an important role in characterizing neurological consequences of HI-BI (such as white matter injury and abnormal brain metabolites). It can identify brain tissues that have died but often cannot identify tissues that are dying or reflect the state of cerebral oxygen metabolism.
However, SWI can provide the missing pieces of information, in that it can provide additional information on cerebral oxygen metabolism, identifying brain tissues in an ischemic state because of its sensitivity to paramagnetic substances, particularly intravenous deoxyhemoglobin. In terms of the deep cerebral venous system, quantity of deoxyhemoglobin reflects magnitude of extraction, or veno-occlusion. This gives us a look at cerebral metabolism, and we feel that these appearances will correlate with poor outcomes.

6. POV Scores 1 2 3 4
Susceptibility-weighted axial images illustrate the seven “prominence of vein” categories, with emphasis on the disc-modulating veins system.
(A) Category 1, absent (no visible deep medullary).
B) Category 2, faint (visible deep medullary veins, nearly absent subependymal veins, and a few nonprominent cortical veins).
(C) Category 3, minimal (several definite, fine, light gray deep medullary veins are visible and limited to the deep white matter; the subependymal veins are present but not prominent, and cortical veins are occasionally prominent).
(D) Category 4, mildly prominent (many dark, distinct deep medullary veins are visible, either diffusely or regionally; the deep medullary veins are wider and better demarcated, but do not extend to the most superficial layers of the deep white matter; the subependymal veins are usually prominent, and a few cortical veins may be prominent). (E)

7. POV Scores 5 6 7
(E) Category 5, moderately prominent (the deep medullary veins are even darker, more numerous, and wider, extending into the superficial white matter, either diffusely or regionally; the subependymal veins are prominent and more cortical veins may be prominent).
(F) Category 6, severely prominent (numerous deep medullary veins are very dark and extend through the superficial white matter nearly to the cortex, either diffusely or regionally; subependymal veins and cortical veins are very prominent; a dark background blush may be evident in the white matter).
(G) Category 7, extremely prominent (numerous, thick, dark deep medullary veins extending to the cortex; they may be irregular; the subependymal and cortical veins are prominent).

8. Normal
Abnormal
2-4 Normal
1, 5-7 Abnormal

9. Outcomes Measurement Poor Outcomes Seizure Death
With POV established as the exposure, the outcomes were defined as death or seizure disorder on discharge (also if the baby was discharged on anti-epileptic medications), and this was defined as a poor outcome.
Death

10. Data Collection 77 patients Inclusion Criteria Exclusion Criteria
77 patients were included in this study.
The inclusion criteria was evidence of neonatal hypoxic-ischemic injury within the first 3 days
after birth, defined by at least one:
- Neonatal encephalopathy
- 5-minute Apgar score of <5,
- Umbilical artery pH <7.1
Umbilical cord base excess >- 10
as well as MRI and SWI
-Between 0-60 days after birth.
Exclusion
-Proven congenital malformations, infection, or metabolic disease.

11. Statistical Analysis Fischer’s Exact Test and Student t-test
Cochron-Mantel-Haenszel
Cool and Noncooled
Fisher exact test was used to compare binary variables and student t-test was used to compare age between cooled and non-cooled neonates. Stratified analysis between cooled and non-cooled neonates using Cochron-Mantel-Haenszel test.
Statistical significance was defied at p <0.05 level.

12. Results n=77 (%) Mean Age +/- SD (days) 8 +/-3.75 Hypothermia Therapy
37 (48.1)
Abnormal prominence of veins score
19 (24.7)
Diagnosis of seizure disorder
38 (49.3)
Death
9 (11.7)

13. Results Cooled n=37 (%) Non-cooled n=40 (%) p-value
Mean Age +/- SD (days)
8.6 +/- 4.1
7.4 +/-3.3
0.16
Abnormal prominence of veins score
3 (8.1)
24 (60)
<0.001
Death
6 (15)
0.48
Diagnosis of seizure disorder
18 (48.7)
20 (50)
1.00

14. Results
p value: < .001
There is an association between POVS and outcomes in our cohort and it is statistically significant.

15. Results Poor Outcomes Good Outcomes Odds Ratio (95% CI) p-value
Abnormal POVS 16 3
5.71 ( )  
<0.001
Normal POVs 28 30
The odds ratio and 95%CL were calculated.
Neonates with abnormal POVS are 5.7 times more likely to have poor neurological outcomes when compared to neonates with normal POVS.

16. Results Noncooled Cooled p-value =0.50
Stratified analysis in cool and noncooled patients separately reveals that the babies with abnormal POVS, more likely to have poor outcome with the stratified analysis. However, there is no statistical differences between the stratified analysis and the crude analysis. (the odds ratio, with p value of 0.5)
Graphs show that non-cooled neonates who have abnormal POVS are 6.07 times more likely to have poor outcomes when compared to non-cooled neonates with normal POVS
And the cooled neonates who have abnormal POVS are 7.8 times more likely to have poor outcome when compared to cooled neonates with normal POVS.
*Breslow-Day Test for Homogeneity of the Odds Ratios showed that hypothermia was not a confounder (p= 0.50).
OR: 6.07
[ ]
OR: 7.80
[ ]
Noncooled
Cooled
p-value =0.50

17. Discussion
In our subject population, there was an association with abnormal POV with outcomes.
Non-cooled neonates who suffered HI-BI have more abnormal POV appearance as compared to cooled neonates.
Hypothermia therapy does appear to affect the association.

18. Conclusion
Abnormal POV score is associated with poor outcomes in neonates with HIBI. Potential biomarker in this population with potential to guide future HIBI therapies.
Abnormal POV score, which reflects extreme or impaired oxygen extraction, is associated with poor outcomes in neonates with HIBI in both cooled and non-cooled neonates.
Potential biomarker in this population, with potential to guide future HIBI therapies because of its potential to provide physiological information that conventional MR sequences cannot provide.

19. References
1. Kurinczuk JJ, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early human development 2010;86: Fatemi A, Wilson MA, Johnston MV. Hypoxic-ischemic encephalopathy in the term infant. Clinics in perinatology 2009;36:835-58, vii. 3. Corbo ET, Bartnik-Olson BL, Machado S, et al. The effect of whole-body cooling on brain metabolism following perinatal hypoxic-ischemic injury. Pediatric research 2012;71:85-92.

20. p-value Abnormal POVS 16 3 5.71 (1.5-21.7) <0.001 7.32 (1.7-30.5)
Poor Outcomes
Good Outcomes
Odds Ratio
(95% CI)
p-value
Adjusted Odds Ratio
Abnormal POVS 16 3
5.71 ( )      
<0.001
7.32 ( )
Normal POVs 28 30
The adjusted odds ratio and 95%CL were calculated using logistic regression analysis, adjusting for hypothermia therapy. The association between POVS and outcomes was tested using Fisher’s Exact test. Statistical significance was defied at p <0.05 level.