This document summarizes recent literature on the treatment of traumatic brain injury (TBI). It reviews guidelines for managing TBI, including avoiding hypotension and hypoxia. It discusses studies on fluid resuscitation with hypertonic saline or plasma. The document also summarizes three important TBI studies: the BOOST-II trial on brain oxygen monitoring, the POLAR trial on early hypothermia, and the EPIC statewide study implementing prehospital TBI guidelines. Throughout, it notes limitations of animal studies in reproducing complex human TBI pathophysiology and outcomes.

1. R ADAMS COWLEY SHOCK TRAUMA CENTER
Rapid Review: Traumatic Brain
Injury
Sam Galvagno, DO, PhD, FCCM
Col, USAF, MC, SFS
Associate Professor
Medical Director, Lung Rescue Unit (LRU)
University of Maryland School of Medicine
R Adams Cowley Shock Trauma Center
Baltimore, MD, USA

2. R ADAMS COWLEY SHOCK TRAUMA CENTER
Disclosures
• United States Air
Force Reserve
• UpToDate®
Author
• Department of
Defense Funding

3. R ADAMS COWLEY SHOCK TRAUMA CENTER
Objectives
• Review treatment guidelines for the
management of TBI
• List evidence-based interventions for TBI
• Assess key publications published in the
last year

4. R ADAMS COWLEY SHOCK TRAUMA CENTER
R Adams
Cowley
Shock
Trauma
Center

5. Context
• TBI + hemorrhage  leading
cause of death from injuries
• Paucity of data to help guide
decision making
– MAP target? Monitoring
modalities?
– Physiological phenotypes?
Dutton RP. J Trauma 2010.
Eastridge BJ. J Trauma Acute Care Surg 2012.
Bogert JN. J Intensive Care Med 2016.
Brasel KH. J Trauma 2011.
Galvagno SM. J Trauma Acute Care Surg 2017.
Bouzat P. Ann Intensive Care 2013.

6. Pathophysiology
Genet GF. J Neurotrauma 2017.
Bambbakidis T. J Neurotrauma 2016.
Balbino M. J Trauma 2010.
Karri J. Shock 2017.
Bouzat P. Ann Intensive Care 2013.
Silleson M. Dan Med 2014.
Leung LY. J Neurotrauma 2013.

7. R ADAMS COWLEY SHOCK TRAUMA CENTER
50% dead if hypoxic
53% dead if hypotensive
75% dead if had both
24% dead if had neither

8. Hypotension and Hypoxia
Spaite DW. Ann Emerg Med 2017.

9. R ADAMS COWLEY SHOCK TRAUMA CENTER
Recommended “Bundles”
• Activate MTE protocol
 1:1:1 transfusion ratio
• Measure lactate or base
excess
• Measure coagulopathy with
viscoelastic methods
• Do not use large volumes of
crystalloids (<3 L / 6 hours)
• Avoid & treat hypoxia (avoid
hyperoxia)
 PaO2 > 60 mm Hg or SpO2 > 90%
• Avoid hypotension
 SBP > 90 mm Hg
• Avoid hyperventilation
 PaCO2 goal: 35-45 mm Hg
• Evaluate and treat intracranial
hypertension
 Treat ICP > 20 mm Hg
 Maintain CPP 50-70 mm Hg
Shafi S. J Trauma Acute Care Surg 2016.
Proctor JL. J Trauma Acute Care Surg 2015.
Blasiole B. Anesthesiology 2013.

10. Vasopressin?
• Pharmacologic amplification of neuroendocrine stress
response
– Levels increase 45-500x in multiple trauma
• Animal studies: early vasopressin rapidly corrects CPP
and reduces fluid requirements
• Human study: > 2x adjusted risk for mortality
– Increased mortality regardless of type of vasopressor
Sperry JL. J Trauma 2008.
Cossu AP. BioMed Res Internat 2014.
Gupta B, J Anaestheiol Clin Pharmacol 2017.
Sanui M. Crit Care Med 2006.

11. R ADAMS COWLEY SHOCK TRAUMA CENTER
2017
Brain Trauma Foundation Guidelines
• EVD use: GCS < 8 AND
abnormal CT
• Hyperventilation only to
temporize
 Prolonged hyperventilation
with PaCO2 of < 25 mm Hg
NOT recommended
• PaCO2 target: 35-45
• CPP target: 60 – 70 mm Hg
• SBP ≥ 100 mm Hg for patients
50 to 69 years old
• SBP ≥ 110 mm Hg for patients
15 to 49 or > 70 years old
• Hyperosmolar therapy with mannitol
or hypertonic saline may lower
intracranial pressure, but there is
insufficient evidence to support the
use one rather than the other
• Hypothermia NOT recommended
• Phenytoin vs. levetiracetam? Early
administration (<7 days)
recommended to prevent seizures
• Brain tissue oxygen monitoring is no
longer recommended due to
insufficient evidence
• A jugular venous saturation < 50%
may be a threshold to avoid in order
to reduce mortality and improve
outcomes
Stein SC. J Neurosurg 2010.
Alail AS. J Neurotrauma 2013.
Talving P. J Neurosurg 2013.
Carney N. BTF Guidelines, Fourth Edition. Neurosurgery 2017.

12. Fluid Choice
• 3% hypertonic saline
– Less fluid required
– Lowers ICP
– Maintains CPP
• 3% + LR
– Blunts calcium influx in early stage of TBI
Dekker SE. Surgery 2014.
Jung A, Brain Inj 2018.
Pinto FC. J Trauma 2006.
Balbino M. J Trauma 2010.

13. Hypertonic: Molecular Benefits
Galvagno SM. Anesthesiol Clin 2013.

14. Valproic Acid
• Histone deacetylase inhibitor
– Down regulates cytokine release
– Modulates transcription, prosurvival
pathways, expression of
inflammatory pathways
• Attenuates platelet and endothelial
dysfunction
• Consistently safe, decreases brain lesion
size, reduces neurologic injury
IN ANIMAL STUDIES
Halaweish I. Shock 2015.
Nikolian VC. J Trauma Acute Care Surg 2017.
Dekker SE. J Surg Res 2014.
Jin G. J Trauma Acute Care Surg 2012.
Weykamp M. J Surg Res 2018.

15. Plasma Resuscitation
• Both FFP and LP decrease brain lesion
size and improve neurological
recovery
– FFP associated with
downregulation of inflammatory
pathway genes
• Pathogen-reduced FFP may decrease
brain edema
• Plasma-treated animals: lower
neurologic severity scores / faster
return to baseline function
Georgoff PE. J Neurotrauma 2017.
Silleson M. J Am Coll Surg 2017.
Halaweish I. J Am Coll Surg 2015.
Halaweish I. J Trauma Acute Care Surg 2016.
Genet GF. J Neurotrauma 2017.

16. R ADAMS COWLEY SHOCK TRAUMA CENTER
3 Important TBI Studies

17. Brain oxygenation optimization in Severe Traumatic Brain Injury (BOOST-II)
Okonkwo DO, Shutter LA, Moore C, et al. .
10 Trauma Centers (Pittsburgh, Washington, UT Southwestern, Cincinnati, Miami, Stanford, Ohio State, Temple, Thomas Jefferson, Baylor, Penn)
Crit Care Med 2017; 45: 1907-1914.
• 2 arm, prospective RCT, 10 level 1 trauma centers
• ICP + PbtO2 vs. ICP monitor
• Interventions based either/or ICP ≥ 20 or PbtO2 < 20
• Primary outcome: efficacy of PbtO2 treatment
• PbtO2 group ↓ hypoxia by 66% and ↓ depth of hypoxia
by 77%
• Trend toward lower mortality (34 vs. 25%)

18. R ADAMS COWLEY SHOCK TRAUMA CENTER
Brain oxygenation optimization in Severe Traumatic Brain Injury (BOOST-II)
Okonkwo DO, Shutter LA, Moore C, et al. .
10 Trauma Centers (Pittsburgh, Washington, UT Southwestern, Cincinnati, Miami, Stanford, Ohio State, Temple, Thomas Jefferson, Baylor, Penn)
Crit Care Med 2017; 45: 1907-1914.

19. Brain Tissue Oxygenation:
What is it and does it tell us?
• Clark electrode that assesses tension
of oxygen in a small region (17mm)
around the distal end
• Normal level PbtO2 is 23 ± 7 mm Hg
• Is this value similar to PaO2, SpO2, or
something else????
• What influences the make up of
PbtO2?
– Blood flow
– Arterial content of oxygen
– Metabolism
– Diffusion
Critical Care Medicine 2008; 36.

20. R ADAMS COWLEY SHOCK TRAUMA CENTER

21. R ADAMS COWLEY SHOCK TRAUMA CENTER
Effect of early sustained prophylactic hypothermia on neurological
outcomes among patients with severe traumatic brain injury (POLAR)
Cooper JC, Nichol AD, Bailey M, et al.
ANZIC Research Centre, Monash University, Melbourne, Australia
JAMA 2018; 320(21): 2211-2220.
• Multicenter RCT, hypothermia vs. normothermia
• Bolus 2000 mL 4o C 0.9% saline (target 33-35o C)
• Primary outcome GOSE at 6 months post injury

22. R ADAMS COWLEY SHOCK TRAUMA CENTER
The Excellence in Prehospital Injury Care (EPIC) study
Spaite DW, Bobrow BJ, Keim SM, et al. .
University of Arizona, Tucson, AZ
JAMA Surg 2019.
• Objective: Implement guidelines at a statewide level
and assess for effectiveness
• 4 main interventions:
• 1. Treat hypoxia
• 2. Airway interventions
• 3. Prevent hyperventilation
• 4. Avoid hypotension (fluids)
• 21,852 patients

23. R ADAMS COWLEY SHOCK TRAUMA CENTER
The Excellence in Prehospital Injury Care (EPIC) Study
Spaite DW, Bobrow BJ, Keim SM, et al. .
University of Arizona, Tucson, AZ
JAMA Surg 2019.

24. R ADAMS COWLEY SHOCK TRAUMA CENTER
Thank you!
sgalvagno@som.umaryland.edu

25. Problems with Animal Studies
• Animals anesthetized
• Hypercoagulable (swine)
• Experimental setup – “controlled” condition
– To maximize reproducibility / standardization
• Focal vs. diffuse TBI
• Poor reproducibility with uncontrolled
hemorrhage models
Combes RD. Altern Lab Anim 2013.
Namas R. LJM 2009.
Angoa-Perez M. J Neurochem 2014.