1. Status of HBOCs for TBI Indication
Paula F. Moon-Massat, DVM, DACVAA
Neurotrauma Dept., NMRC
Silver Spring, MD
Disclaimer
The views expressed in this presentation are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. This presentation was prepared as a part of officials duties. Title 17 USC provides that Copyright protection is not available for any work of the United States Government, defined as work prepared by a military service member or employee of the U.S. Government as part of their official duties.

2. Rationale for TBI Benefit
Improved neurologic outcome
PtbO2
Duration hypoxemia
Fluid needs balanced
CPP (oxygen delivery)
Cerebral edema
HBOC characteristics

3. Clinical TBI HBOC Data Historical Currently DCLHb No TBI trials
Exclusion criterion
Compassionate Use
Cerebral ischemia trial

4. TBI-Related Clinical Trial
[Prolong Pharma]
Pts at risk for delayed cerebral ischemia following subarachnoid hemorrhage
Exclusion: hemorrhage 2° to trauma 
Endpoint
Measure 1°
PbtO2 and CBF 2°
Neurological function
Size of cerebral infarction

5. Preclinical TBI HBOC Data
TBI ± Trauma Studies N
Species
TBI 2
rat
TBI + Trauma 9
7 swine
2 rodent
Relevant Others w/ Brain Data N
Species
Trauma [4 have brain data]
4 of 16
swine
Hemodilution 4
3 swine, 1 rat
CPB 2
Top-load 1
rat
11 – 22 Studies w brain data ( )

6. HBOCs in TBI Preclinical Studies
HBOC-201, HBOC-301 (HbO2 Therapeutics)
MP4CO-NP (Sangart)
M101 (Hemarina)
Oxyvita, Oxyvita C (OXYVITA Inc.)
PNPH (Synzyme)
Sanquinate (Prolong Pharmaceuticals)

7. HBOC-201 Trauma-only Swine Survival (N = 15)
Less severe More severe

8. HBOC TBI + Trauma Survival (6 swine, 2 rodent)
Less severe More severe

9. Collective Summary * (any species, HBOC)2 4 8 1 12 3
PtbO2: 12/
CPP: 8/8 …
CBF: 1/5 …
ICP: 4/7…
CVH: 4/4 …
CVMO2: 2/2 …...
Risk = Benefit
* TBI (2), TBI + Trauma (10), Trauma (4), CPB (2), Dilution (3)

10. Collective Summary * (Cont.)4 2 1 9
Risk = Benefit
Wean/Extubate: 2/3…...
Biomarkers: 1/1…......
Fluids: 9/9 …
Edema: 2/2 …
Contusion: 1/2 …
Histopath: 4/6 …
* TBI (2), TBI + Trauma (10), Trauma (4), CPB (2), Dilution (3)

11. Vasoconstriction Tissue-specific?
Type of Study
Tissue
Effect of HBOC
Studies
(N)
Microvascular
(1° rodent)
Muscle Mesentery
Vasoconstriction 18
Vascular ring
(bovine)
Lung
Heart 1
(rat)
Brain
No effect 5

12. Blood flow - Tissue-specific?
With HBOC:
Reduced muscle
Unchanged brain (all other tissues)
(Mongan, 2009)

13. HBOC Summary TBI Indication
Clinical
Sparse
2 Compassionate Use – promising/cautionary
Pre-clinical
Acute or delayed
Localized or global
Brain vs. systemic differences
Risk/Benefit
No cerebral pial vasoconstriction
CBF not skeletal blood flow
Other (i.e., enzyme induction)

15. Future HBOC Studies Information on Optimizing the products
Autoregulation (CVH, BP, O2)
Simultaneous and concurrent measurements
Type of TBI (penetrating, blast, mild)
Cognitive tests, behavior, longer duration studies
Optimizing the products
Dose
Timing
Frequency

16. TBI Compassionate Use JW, MVA (2009): D7: PbtO2 after HBOC
D9: Edema, death 12 h after HBOC
Reperfusion injury?
JW, MVA (2002):
D2-5: HBOC for anemia
D19: Discharged
Marinaro, 2009; Cothren, 2002