Medicating the Melon - Mayo Clinic...Medicating the Melon: Adjunctive Therapy after Traumatic Brain Injury Kirstin Kooda, Pharm.D., BCPS, BCCCP Critical Care Pharmacist Pharmacy Grand

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


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


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:


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


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?


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


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


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


• 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


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.


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


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


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


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


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


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


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?


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


Which is an example of secondary injury in acute TBI?• 1. Traumatic hemorrhage

• 2. Penetrating injury

• 3. Diffuse axonal injury

• 4. Cellular mediated toxicity


Progesterone has an important role in current standard of care after TBI• True

• False


What are potential options for paroxysmal sympathetic hyperactivity?• A. Propanolol and clonidine

• B. Antipsychotics

• C. Gabapentin

• D. Mannitol

• E. A & C

• F. A & B


Questions and [email protected]


Medicating the Melon - Mayo Clinic...Medicating the Melon: Adjunctive Therapy after Traumatic Brain Injury Kirstin Kooda, Pharm.D., BCPS, BCCCP Critical Care Pharmacist Pharmacy Grand

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