The document discusses pharmacotherapies for traumatic brain injury (TBI) that pharmacy students should know, including their mechanisms, efficacy, and adverse effects. It highlights the distinction between primary injury at impact and secondary injury which develops thereafter due to factors like hypotension and increased intracranial pressure. Treatment options like mannitol and barbiturates are evaluated, but the evidence for their effectiveness in TBI management remains inconclusive.

1. Agents for Traumatic Brain
Injury
Brian J. Piper, Ph.D., M.S.
piperbj@husson.edu
February 15, 2013

2. Objective
• Pharmacy students should be familiar with
different pharmacotherapies used with brain
injury including their:
– mechanisms of action
– relative efficacy
– adverse effects

3. falls motor-vehicle/assaults falls/motor-vehicle
Burns & Hauser (2003) Epilepsia, 44(S10), 2-10.

4. Individual Differences following TBI
apoE4+ (N=27) apoE4- (N=42)
Unconscious for >1 week 77.8% 38.1%*
Dysarthria 63.0% 33.3%*
Overall Function: excellent 3.7% 31.0%*
* p < .05
Friedman et al. (1999). Neurology, 52(2), 244-250.

5. Secondary Injury
• All brain damage does not occur at the
moment of impact (primary injury) but
evolves over the ensuing hours and days
(secondary injury).
• The injured brain is extremely vulnerable to
hypotension, hypoxia, and increased
intracranial pressure which are causes of
secondary injury.

6. ↓ Blood Pressure: Tx-Dopamine
• MOA: D1 > α1
• Effects: ↑ systolic bp

7. Intra-Cranial Pressure
• There is only one way out of the intracranial vault, the
opening at the base of the skull: foramen magnum

8. ↑ Intracranial Pressure: Tx-Mannitol
• History: sugar derivative of mannose-1961
• Frequency: majority of trauma centers
• Effect:
– immediate ↓ ICP; withdrawal ↑ ICP
– renal failure
Grande & Romner (2012). J Neurosurg, 24(4), 407-412.

9. Mannitol versus Hypertonic Saline
->
Vialet et al. (2003). Critical Care Medicine, 36, 795-800.

10. Mannitol versus Hypertonic Saline
Vialet et al. (2003). Critical Care Medicine, 36, 795-800.

11. ↑ Intracranial Pressure: Tx-
Barbiturates
• Indications:
– ↑ ICP refractory to other treatments
• Frequency: minority of trauma centers
• Rationale:
– ↓ neuron activity ↓ metabolic demands
– ↓ free radical formation
• Effect:
– immediate ↓ ICP; hypotension (25%)
Roberts & Sydenham (2012). Cochrane Database of Systematic Reviews, 10.1002/14651858.CD000033.pub2.

12. Absence of evidence ≠
Evidence of absence
• “There is insufficient reliable evidence to
make recommendations on the use of
mannitol in the management of patients with
traumatic brain injury.”
• “There is no evidence that barbiturates
improve outcomes in people with acute brain
injury.”
Wakai et al. (2008). Cochrane Database of Systematic Reviews, 10.1002/14651858.CD001049.pub4.
Roberts & Sydenham (2012). Cochrane Database of Systematic Reviews, 10.1002/14651858.CD000033.pub2.

13. Propofol Factoids

14. Propofol
• Indication: hypnotic (not analgesic)
• MOA:
– GABAA agonist
– NMDA antagonist
– ↓ glutamate release
– ↓ excitotoxicity/antioxidant
• General: consistent, rapid loss (& recovery) of
consciousness, amnesic, excellent safety margin
• Other ingredients: egg phosphatate & edetate
disodium (EDTA)
Example 0:35 to 1:20: http://www.youtube.com/watch?v=kmMFLOXLD-Q
Kotani et al. (2008). CNS Neuroscience & Therapeutics, 10.1111/j.1527-3458.2008.00043.x

15. Propofol Infusion Syndrome
• Combination
– critically ill children + long-term/high-dose propofol
– catecholamines or steroids too
• Symptoms:
– rhabdomyolasis
– renal/cardiac failure
Vasile et al. (2003). Intensive Care Medicine, 29, 1417-1425.

16. Memory
• ------------------------|----------------------------
trauma
• Anterograde Memory: propofol decreases
memory of events that happen post-trauma
• Retrograde Memory: propofol increases
memory of events that occur pre-trauma

17. Passive Avoidance
Day 1: Training
Drug
Day 3: Test
Hauer et al. (2011). Anesthesiology, 114(6), 1380 – 1388.