Agents for Traumatic Brain Injury

Brian J. Piper, Ph.D., M.S.piperbj@husson.edu

February 15, 2013

Objective

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

Burns & Hauser (2003) Epilepsia, 44(S10), 2-10.

falls motor-vehicle/assaults falls/motor-vehicle

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%*

Friedman et al. (1999). Neurology, 52(2), 244-250.

* p < .05

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.

↓ Blood Pressure: Tx-Dopamine

• MOA: D1 > α1

• Effects: ↑ systolic bp

Intra-Cranial Pressure

• There is only one way out of the intracranial vault, the opening at the base of the skull: foramen magnum

↑ 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.

Mannitol versus Hypertonic Saline

Vialet et al. (2003). Critical Care Medicine, 36, 795-800.

->

Mannitol versus Hypertonic Saline

Vialet et al. (2003). Critical Care Medicine, 36, 795-800.

↑ 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.

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.

Propofol Factoids

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)

Kotani et al. (2008). CNS Neuroscience & Therapeutics, 10.1111/j.1527-3458.2008.00043.x

Example 0:35 to 1:20: http://www.youtube.com/watch?v=kmMFLOXLD-Q

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.

Memory

• ------------------------|----------------------------

• Anterograde Memory: propofol decreases memory of events that happen post-trauma

• Retrograde Memory: propofol increases memory of events that occur pre-trauma

trauma

Passive Avoidance

Day 1: Training DrugDay 3: Test

Hauer et al. (2011). Anesthesiology, 114(6), 1380 – 1388.