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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
Disclosures• No financial relationships pertinent to this
session
• Off label use of medications will be discussed
©2012 MFMER | slide-2
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
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.
BrainBrain
Primary Injury
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
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.
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
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.
Can we use medication to minimize damage and alter these outcomes?
©2012 MFMER | slide-10
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
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.
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.
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.
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
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.
Brain
Blood
CSF
Brain
Blood
ICP ↑ CPP ↓
ICH = ICP > 20 mm Hg
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.
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.
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
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.
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
Standard of Care and Novel Therapies in Progression of TBI
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.
©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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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
Progesterone has an important role in current standard of care after TBI• True
• False
©2012 MFMER | slide-38
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
Questions and Discussionkooda.kirstin@mayo.edu
©2012 MFMER | slide-40
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