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Medicating the Melon: Adjunctive Therapy after Traumatic Brain InjuryKirstin Kooda, Pharm.D., BCPS, BCCCPCritical Care PharmacistPharmacy Grand Rounds January 24th, 2017
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Disclosures• No financial relationships pertinent to this
session
• Off label use of medications will be discussed
©2012 MFMER | slide-2
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Objectives • Review the pathophysiology and clinical course
of traumatic brain injury (TBI)
• Discuss the pharmacology of the current standard of care following TBI
• Identify potential novel pharmacotherapy that can impact outcomes
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Background• Major cause of morbidity and mortality ages 18-
45
• Long-term consequences of injury• Reduced ability to work and care for own
needs• Mood instability• High societal cost
©2012 MFMER | slide-4
Centers for Disease Control and Prevention. (2015). Report to Congress on TraumaticBrain Injury in the United States: Epidemiology and Rehabilitation. National Center for Injury
Prevention and Control; Division of Unintentional Injury Prevention. Atlanta, GA.
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BrainBrain
Primary Injury
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Secondary Injury• Result of pathological processes started at time
of injury• Delayed clinical impact
©2012 MFMER | slide-6Werner C and Engelhard K. British Journal of Anaesthesia. 99(1);4-9:2007.
Stage 1 Stage 2Ischemia Ca2+ influx
Lactic acidosis Terminal membranedepolarization
Failure of membrane ion pumps Glutamate release
NDMA activationIncreased FFA and free radicals
Neuron necrosis and apoptosis
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Severity of Injury
Criteria Mild Moderate SevereStructural Imaging Normal Normal or
abnormalNormal or abnormal
Loss of consciousness < 30 minutes 30 minutes to 24
hrs > 24 hrs
Post traumatic amnesia (PTA) 0-1 day > 1 and < 7 days > 7 days
Glasgow Coma Scale 13-15 9-12 3-8
Abbreviated Injury Scale:
Head1-2 3 4-6
©2012 MFMER | slide-7
Centers for Disease Control and Prevention. (2015). Report to Congress on Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation. National Center for Injury
Prevention and Control; Division of Unintentional Injury Prevention. Atlanta, GA.
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Consequences?• 3.0-5.3 million in US affected by TBI disability
• Long term behavioral changes with mild or moderate injury
• Severe injury:
©2012 MFMER | slide-8
Jiang JY, et al. J Neurotrauma. 2002;19(7):869.
Schuller JS, et al. Vital Health Stat. 2012;10(252).
DeathVegetativeDisabilityFunctional
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Rating Scales and Defining Outcomes
©2012 MFMER | slide-9
GCS Glasgow Outcome Scale (6 months)
Disability Rating Scale
Total: 3-15 1 = death 0-29; higher worse
Motor: 1-6 2 = vegetative Consciousness
Eye 1-4 3 = dependent for daily activities Cognitive ability
Verbal 1-5 4 = Someindependence Dependence on others
5 = Full independence Employability
Carney N, et al. Neurosurgery. 2016.
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Can we use medication to minimize damage and alter these outcomes?
©2012 MFMER | slide-10
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Acute Pharmacology• Management immediately after injury
• Recall acute physiology
Goal Mechanism
Minimize ICP elevation Adequate Sedation
Manage ICH Hyperosmotic Therapy
Optimize CPP Vasopressors
Ameliorate cellular toxicity Progesterone or NAC?
Carney N, et al. Neurosurgery. 2016.
ICP: intracranial pressure; ICH: intracranial hypertension; CPP: cerebral perfusion pressure; NAC: n-acetylcysteine
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Sedation
©2012 MFMER | slide-12
Drug Evidence
Propofol• ↓ ICP
• No impact on mortality, 6 month outcomes• Guideline recommended
Barbituates • Reserve for refractory cases
Opioids• High bolus doses ↑ ICP
• Pain control in multi-trauma important• Fentanyl primary
Benzodiazepines • Generally avoided due to long duration of action• Consider midazolam if CI to propofol
• Goal: minimize ICP elevation in acute phase post TBI
CI: contraindications Carney N, et al. Neurosurgery. 2016.
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Dexmedetomidine?
Design • Single-center, prospective, observationalPopulation • Adults with TBI
• Need for mechanical ventilation > 24 hours
• Receiving continuous infusion sedationIntervention • Dexmedetomidine
• Dexmedetomidine AND propofol• Propofol• Neither
Primary Outcome • Mean time in target RASS (-2 to 0) based on patient-days (1,028 for 198 patients)
Secondary Outcomes
• Max ICP for each group• Adverse events
Pajoumand M, et al. J Trauma Acute Care Surg. 2016:81(2);345-351.
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Results
02468
1012141618
Tim
e (h
)
Mean Time in Goal RASS
©2012 MFMER | slide-14
0
5
10
15
20
25
SBP MAP
% P
atie
nts
Hypotension
DEX
PROP
DEX +PROPNeither
Pajoumand M, et al. J Trauma Acute Care Surg. 2016:81(2);345-351.
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Cerebral Perfusion Pressure
©2012 MFMER | slide-15
• MAP – ICP = CPP
• Normal CPP > 50 mmHg; TBI goal 60-70 mmHg
Carney N, et al. Neurosurgery. 2016.CPP
CB
F
↓ CPPVasodilate↑ CBV↑ ICP
↑ CPPVasoconstrict
↓ CBV↓ ICP
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The place of vasopressors• No specific commentary in 2016 guidelines
• CPP goal 60-70 mmHg• SBP goal ≥ 100mmHg in 50-69 yo• ≥ 110 mmHg in 15-49 yo or ≥ 70 yo
• Vasopressors reasonable if hypotensive• No specific data exists regarding selection
• Norepinephrine, phenylephrine, vasopressin?
©2012 MFMER | slide-16Carney N, et al. Neurosurgery. 2016.
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Brain
Blood
CSF
Brain
Blood
ICP ↑ CPP ↓
ICH = ICP > 20 mm Hg
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Mannitol and Hypertonic Saline• Administer if ICP > 22 mmHg for prolonged
period of time• Unclear if either agent better for long-term
outcomes
• Selection based on individual patient variables (sOsm, renal function, Na level)
©2012 MFMER | slide-18Carney N, et al. Neurosurgery. 2016.
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Adjuncts Immediately After Injury• Attempt to mitigate spread of cellular toxin
mediated damage
• Progesterone neuroprotective via multiple mechanisms
• Early RCT revealed significant improvement in functional outcome and decrease in mortality
• HR 0.43 (95% CI 0.18 – 0.99)• Moderate TBI improved GOS-E and DRS
©2012 MFMER | slide-19Wright DW, et al. Ann Emerg Med. 2007:49(4);391-402.
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Progesterone – Unfulfilled Potential
Skolnick BE, et al. N Engl J Med.371;26:2467-2476.
Design • Multi-national, prospective, randomized
Population • 1195 adults with severe TBI (age 16-70, GCS ≤ 8)
Intervention • 597 patients: progesterone 0.71 mg/kg load, followed by 0.5 mg/kg/hr for 119 hours
• 598 patients: placebo
Primary Outcome • 6 month Glasgow Outcome Scale
Secondary Outcomes • 1 and 6 month mortality• 3 month Glasgow Outcome Scale• Safety and monitoring endpoints
No Difference in Any Measured Outcome
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N-Acetylcysteine• Neuroprotective in rodent studies of brain injury
• Antioxidant, anti-inflammatory, acts on glutamate receptors
• Some evidence to reduce hearing loss in humans
Wells, et al. Critical Care 2012, 16:R193.
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Promising Initial Results
Hoffer ME, et al. PLOS ONE. 2013;8(1):e54163.
Design • Prospective, randomized, double blind
Population • 81 adults with mild TBI after blast injury in Iraq
Intervention • 40 patients: NAC 4g load, then 2g BID x4 days, then 1.5g BID x 3 days
• 41 patients: placebo
Primary Outcome • % of subjects free from all mild TBI symptoms at 7 days
Secondary Outcomes • Balance dysfunction• Absence of headache, confusion, memory
problems, abnormal sleep• % of subjects free from all mild TBI symptoms
at 3 daysResults • OR 3.6, p = 0.0062 for symptom resolution
with NAC• Time of treatment and distance from blast also
significant
Potentially beneficial, further data needed
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Standard of Care and Novel Therapies in Progression of TBI
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Paroxysmal Sympathetic Hyperactivity• 8-30% severe TBI
• True incidence unknown, historically ill-defined
• Sympathetic storm, dysregulation, dysautonomia (+31 other names)
• Increased morbidity, healthcare cost, longer hospitalization, poor outcomes
Baguley IJ, et al. J Neurotrauma. 2014:31; 1515-1520.
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©2012 MFMER | slide-25
Key Criteria Possible MechanismsIntermittent episodes with
resolution in betweenExcessive sympathetic
response to stimuliContinues for ≥ 3 days Lack of inhibitory neurons
No resolution with differential diagnosis
treatment
Enhanced glutamate transmission
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Translation of Protective Findings• Multiple retrospective studies link βB pre-injury
with improved survival
• Potentially related to decrease in PSH episodes
• Clonidine enhances central negative feedback mechanisms via α2
• Dexmedetomidine theoretically carries same benefit
©2012 MFMER | slide-26Heffernan DS, et al. J Trauma. 2010;69(6):1602-1609.
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DASH Published Protocol
©2012 MFMER | slide-27
Design • Prospective, randomized, double blind
Population • Planned 11-41 in each group
Intervention • Propranolol 1 mg IV Q6H, clonidine 0.1 mg Q12H
Primary Outcome • Plasma norepinephrine level on day 8
Secondary Outcomes
• Other physiologic variables• RASS, agitated behavior scale, need for
additional medications• Ventilator days, coma free days, ICU and
hospital LOS
Patel M, et al. Trials. 2012:13;177.
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DASH Preliminary Results• Interval change in primary endpoint to
ventilator-free days• Study halted for futility after 21 in treatment
group and 26 controls
• Trend toward decreased mortality but non-significant (OR 0.71, 95% CI 0.15-3.07)
• Further study and full results needed
Value of Adrenergic Blockade in Acute Severe TBI Questioned. Medscape. Apr 28, 2016.
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Other Potential Management Options
©2012 MFMER | slide-29
Drug Mechanism Benefit Symptoms
Gabapentin GABA agonist Prevent episodes HR, BP, agitation, posturing
Benzodiazepines GABA agonist Prevent/abort episodes
HR, BP, agitation, posturing
Bromocriptine Dopamineagonist Prevent episodes Fever, posturing,
dystonia
Baclofen GABA agonist Prevent episodes Clonus, rigidity, pain
Opiates µ-opioid receptor agonist
Prevent/abort episodes
HR, exaggerated pain response
DantroleneDecreased
muscle contraction
Prevent episodes Posturing, rigidity
Choi HA, et al. Curr Neurol Neurosci Rep. 2013;13:370.
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Delirium in TBI?• Difficult to differentiate delirium from post-
traumatic amnesia• Agitation and behavioral dyscontrol frequent
after TBI
• Antipsychotics?• Rat data suggests harm• Internal study no difference in duration of
post-traumatic amnesia
©2012 MFMER | slide-30
Kline AE, et al. Neuroscience Letters. 2008;448:236-267.Elovic EP, et al. J Head Trauma Rehabil. 2008;23(2):132-135.
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Moving Out of the ICU• 5-15% severe TBI persistent vegetative state
• Possibly related to altered dopaminergic and noradrenergic transmitters
• Amantadine antagonizes NMDA and agonizes dopamine
• Small initial studies suggest improved neurorecovery, but started at variable times after injury
©2012 MFMER | slide-31Meythaler JM, et al. J Head Trauma Rehabil. 2002;17(4):300-313.
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Vegetative on Rehab Admission
©2012 MFMER | slide-32
Design • Prospective, randomized, double blind, multi-center
Population • 184 patients vegetative or minimally conscious 4-16 weeks after TBI with inpatient rehab
Intervention • 87 patients: amantadine for 4 weeks, escalating doses based on DRS
• 97 patients: placebo
Primary Outcome • Rate of improvement of DRS at 4 weeks
Secondary Outcomes • Rate DRS improvement in 2 week washout after treatment
• Adverse events• Exposure to other psychoactive drugs
Results • Significant improvement of DRS with amantadine; effect lost when drug stopped
• 0.24 points per week (p = 0.007)
Giacino JT, et al. N Eng J Med. 2012.366;9:819-826.
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The future of amantadine• Current clinical practice varies with start time
after injury• More data needed
• Consider initiation at 4 weeks post injury if patients minimally conscious or vegetative
©2012 MFMER | slide-33
Meythaler JM, et al. J Head Trauma Rehabil. 2002;17(4):300-313.
Giacino JT, et al. N Eng J Med. 2012.366;9:819-826.
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Prevent other sequelae?
©2012 MFMER | slide-34
Design • Prospective, randomized, double blindPopulation • 94 patients with TBI and PTA resolution in 4
weeksIntervention • 48 patients: sertraline 100 mg QD x24 weeks
• 46 patients: placeboPrimary Outcome • Time to onset of depressive disorder
Secondary Outcomes • Adverse effects• Memory and cognitive function at 24 weeks
Results • NNT = 5.9 to prevent 1 episode of depressive disorder
• Minimal adverse effects• No changes in memory or cognitive function
Jorge RE, et al. JAMA Psychiatry. 2016;73(10):1041-1047.
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Other Ongoing Research
Drug Proposed MechanismMemantine Antagonizes NMDA
Growth hormone Modifies behavioral dysfunctionStatins Reduce inflammatory cytokines
Marijuana Reduce glutamate, free radicals, inflammation
Enzogenol Anti-oxidant, anti-inflammatory
©2012 MFMER | slide-35Gruenbaum SE, et al. CNS Drugs. 2016;30:791-806.
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Conclusions• No single agent impacting outcomes exists
• Complex disease state• Multi-pronged approach needed
• Optimize early care by following guidelines
• Consider amantadine in persistent vegetative state
• Look for further studies related to NAC and PSH
©2012 MFMER | slide-36
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Which is an example of secondary injury in acute TBI?• 1. Traumatic hemorrhage
• 2. Penetrating injury
• 3. Diffuse axonal injury
• 4. Cellular mediated toxicity
©2012 MFMER | slide-37
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Progesterone has an important role in current standard of care after TBI• True
• False
©2012 MFMER | slide-38
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What are potential options for paroxysmal sympathetic hyperactivity?• A. Propanolol and clonidine
• B. Antipsychotics
• C. Gabapentin
• D. Mannitol
• E. A & C
• F. A & B
©2012 MFMER | slide-39