Transcript Improving Cognition After Brain Injury

Appropriate Medication Usage
After TBI: Cognition, Behavior
and Beyond
David X. Cifu, M.D.
The Herman J. Flax, M.D. Professor and Chairman
Department of Physical Medicine and Rehabilitation
Virginia Commonwealth University/Medical College of
Virginia
Guidelines for Medication
Usage After TBI
 Define the problem as objectively and specifically
as possible.
 Use medicines that have some proven efficacy;
don’t just use “something” (e.g. Neurontin).
 Develop clear cut goals and metrics to assist in
determining when to stop treatment.
 Begin low but get to a therapeutic dosing before
abandoning usage.
 Be alert to side effects and undesired effects.
Alterations in Cognition and
Behavior After TBI
 Hypoarousal
 Hypoattention
 Memory Deficits
 Depression
 Delirium
 Agitation
Factors Affecting Cognitive and
Behavioral Function After TBI
 Effects of the TBI
 Medical Instability
– Infection
– Metabolic Disturbances
– Hormonal/NeuroEndocrine Disturbances
– Hypoxia
– Sleep-Wake Disturbances
– Pain
– Seizures
Factors Affecting Cognitive and
Behavioral Function After TBI
 Medications
– Cognitive-Impairing Medications
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Central Acting Antihypertensives (Clonidine)
Central Acting Antispasmodics (Tizanidine)
GI Agents (H2 Blockers, Reglan)
Pain Medications (Narcotics, ? NSAID’s)
Sedatives (Benzodiazepines, Sleep Aids)
Anticonvulsants (Phenytoin, Carbamazepine,
Phenobarbital)
Factors Affecting Cognitive and
Behavioral Function After TBI
– Cognitive-Improving Medications
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Stimulants [Methylphenidate, Dextramphetamine]
Amantadine [Symmetrel]
Bromocriptine [Parlodel]
Selective Serotoninergic Re-Uptake Inhibitors
[Prozac, Zoloft, Paxil,Celexa]
• Combination Antidepressants [Wellbutrin]
• ? Levodopa-Carbidopa [Sinemet]
• ? Anti-Alzheimer's Agents [Aricept, Exelon]
Coma Intervention
 Directed Multisensory Stimulation (DMS)
demonstrated superior (increased
responsiveness, improved RLAS, improved
GCS) versus Non-Directed Stimulation
(NDS) in RLAS II patients
Hall:Brain Injury 1992:6:435-45
Coma Intervention
 Comatose receiving greater therapy
intensity (by 60%) demonstrated a 31%
decrease in length of stay.
Blackerby:Brain Injury 1989;4:167-73
Cognitive Interventions: Hypoarousal
 No reliable data to support the efficacy of
pharmacologic intervention in the comatose
(RLAS I) or vegetative (RLAS II) patient.
All you get is a very “alert”-looking
comatose or vegetative patient.
 Small trials do support use of
neurostimulants (Amantadine 150 mg bid)
in “emerging” patients (RLAS III).
Kaelin: Arch Phys Med Rehabil 1996;77:6-9
Cognitive Interventions: Hypoattention
 Neurostimulants have been demonstrated to
improve attention (and +/- function) in
responsive patients (RLAS IV-VIII) .
 Methylphenidate has the most clinically
demonstrated efficacy for individuals who
have progressed out of coma.
 Dosing 5-30 mg q 7am and 12 pm.
Kaelin: Arch Phys Med Rehabil 1996;77:6-9
Methylphenidate (Ritalin)
 Modes of Action
– Release of Dopamine from reserpine sensitive
presynaptic pool
Braestrup: J Pharm. Pharmacol. 1977, 29: 463 - 470.
– Inhibition of Dopamine uptake
Ferris,Tang: J of Pharmacol. Exp. Ther. 1979, 210: 422 - 428.
– Inhibition of Monoamine Oxidase
Szporny, Gorog: Biochem. Pharmacol. 1961, 8: 263 - 268.
Methylphenidate (Ritalin)
 Pharmacokinetics
– Peak serum levels are reached within 2 hours
(Half life = 2-4 hrs)
– Both a wide inter-individual and intraindividual variability in serum concentrations
exist
– MPH levels are not different in responders and
non-responders
Gualtieri, CT, et al. J of Amer Acad of Child Psych 1982, 21(1): 19-26.
Selective Serotonin Re-Uptake
Inhibitors (SSRI’s)
 Prozac, Zoloft, Paxil, Celexa
 Inhibit CNS reuptake of Serotonin
 Activating antidepressants, however
somnolence present w/ Paxil at doses >20
mg/day
 Increase dosage q 4-6 weeks
 If treating depression, need to commit to 12
month course (or increase recurrence)
Bromocriptine (Parlodel)
 Dopamine receptor agonist
 Adjunctive treatment for Parkinson’s disease
 Suggested for low level patients, however limited
proven efficacy
 Dosage: 2.5-15 mg/day in 2 doses
 Increase dosage weekly
 High incidence of N/V and Headaches with
increasing dosages.
Amantadine (Symmetrel)
 Potentiates Dopamine (mechanism unclear)
 Adjunctive treatment for Parkinson’s
disease (tremor)
 Dosage: 100-400mg/day in bid dosing
(elevated seizure risk above 300 mg/day)
 Increase dosage weekly
 Hallucinations dose limiting side effect.
 Probable efficacy in RLAS III patients.
Other Antidepressants
[Effexor, Wellbutrin]
 Effexor and Wellbutrin inhibit Serotonin, NE, and
Dopamine reuptake = Activating agents
 Effexor Dosage: 75-225 mg/day in 2-3 doses
(Occasional HTN side effects)
 Wellbutrin Dosage: 200-450 mg/day in 3 doses
(May have worsening effects on agitation)
Levodopa-Carbidopa [Sinemet]
 Increases cerebral dopamine
 Suggested for low level patients, however
limited proven efficacy
 Side effects can include dyskinesias and
cognitive changes
 Dosage: 400-1600 mg Levodopa/day in 2-3
doses (tablets contain either 100 or 200 mg
Levodopa)
Anti-Alzheimer's Agents
[Aricept, Exelon]
 Reversible cholinesterase inhibitors =
increases cerebral acetylcholine
 Effective in improving memory in
individuals with Alzheimer’s disease
 Limited research suggests efficacy in TBI
patients
 Extremely expensive, occasional GI side
effects
Treatment Algorithm:
Hypoarousal/Hypoattention
 Day 1
– Define pathology -> CT/MRI, Mechanism of Injury, Secondary BI
– Assess function: DRS, FIM, RLAS (limited efficacy in RLAS I-III)
– Assess medical status -> Infections, Oxygenation, Metabolics,
Fluid Status, Seizures
– Remove medications -> H2 blockers, narcotics, central acting
anti-HTN/GI, Benzodiazepines, Sleepers
 Day 1-4
– Stabilize/Improve medical status
– Assess/Improve sleep-wake cycle: Trazadone, Ambien
– Assess behavior: ABS, Therapy attendance/participation, Attention
to Task
Treatment Algorithm:
Hypoarousal/Hypoattention
 Day 5-10
– Initiate Methylphenidate 5 mg q 7 am and 12 pm, increase 5-10
mg/day to 60 mg maximum
– Monitor behavior and sleep-wake cycle
 Day 10-20
– If Methylphenidate effective, continue at lowest effective dose for
2-3 weeks, then wean off in 2-4 days
– If Methylphenidate ineffective by 30 mg/day, then initiate wean and
begin new agent.
– Recommend: SSRI’s may be appropriate if mild but limited
response to Ritalin ( if depression is suspected, then Ritalin only
effective 4-6 weeks and will need SSRA for 3 months minimum).
Cognitive Interventions: Agitation
 Agitation occurs in >50% of all TBI patients
(RLAS IV), however delirium, seizures, pain,
hypoxia can also manifest with agitation.
 True TBI agitation should be treated with
environmental and behavioral interventions.
 Pharmacologic treatment should only be
implemented in specific behaviors are identified
and goals established.
 Agitation is defined as an Agitated Behavior Scale
score > 21
Cognitive Interventions: Agitation
 Etiologies
– Environmental
– Pain
– Seizure activity
– Delirium (meds, hypoxia, metabolic)
– Inadequate sleep/wake hygiene
… or TBI-related confusion
Cognitive Interventions: Agitation
 Treatment
– Assess for correctable
etiology
• Sleep/Wake Charting
• Medical Management
– Behavioral
• establish desired
behavior
• positive reinforcement
• shaping
• structured therapy
– Agitated Behavior
Scale
• Assess pattern of
agitation
• Documentation
• Evaluate effectiveness
of intervention
– Physical Restraint
– Pharmacologic
• ABS > 28
Agitation: Medications
 Day 1-3 Use prn for ABS >28
– Ativan
– Risperidone
 Day 4+
– Schedule agents if persistent ABS > 28
• Aggression - Beta-Blockers (Propranolol)
• Restlessness - AED’s (Tegretol, VPA)
• Emotional lability - TCA’s (Nortriptyline)
– Wean agent when ABS <21 for 3 days.
Cifu: J NeuroRehabil 1995;5:245-254
Post-Traumatic Seizures:
Background
 TBI-related seizures account for 20% of
symptomatic epilepsy. Hauser: Epilepsia 1991:32;429-45
 PTS accounts for 5% of all cases of epilepsy.
Hauser: Epilepsia 1991:32;429-45
 Late PTS is present in 4-7% all TBI, nearly 20%
rehab TBI, and 35-50% penetrating TBI patients.
Yablon: Arch PM&R 1993:74;983-1001
 EEG has no predictive value for PTS.
Yablon: Arch PM&R 1993:74;983-1001
Prophylaxis for PTS
 73% reduction in early PTS and 50% reduction in
1 year PTS in individuals given phenytoin for 1
week post-TBI.
 No proven benefits to giving prophylaxis >7 days
post-TBI.
Temkin:N Engl J Med 1990:323;497-502
 No benefit to use of up to 1 month VPA.
Temkin: J NeuroSurg 1999:91;593-600
 AANS and AAPM&R recommend 7 days of either
PTH or CBZ post-TBI.
Prophylaxis for PTS
 Do not treat seizure in first 24 hours post-TBI
longer than initial 7 days, unless status epilepticus.
 Seizures in the first week should be treated (1
year) unless there is a non-TBI cause evident
(infection, hypoxia, metabolic, hydrocephalus).
 Seizures after 1 week must be treated for at least 1
year.
GI Ulcer Prophylaxis
 Use of H2-Blockers has been demonstrated
to decrease ICU-related stress ulceration of
the GI tract in specific patient populations
(e.g., burns).
 No specific information in patients with
TBI, with or w/o PEG/J tubes.
GI Ulcer Prophylaxis
 Newer H2-Blockers, while expensive, have
limited CNS effects.
 High risk patients (h/o PUD, h/o GERD,
comatose, > 65 years old) are appropriate
for prophylaxis while in ICU.
 No clear indication for all TBI patients in
ICU.
Spasticity Management
 Treatment should be initiated if the
spasticity is limiting function, ROM, or is
causing pain.
 Potential side effects of treatment must be
weighed against potential benefits.
Spasticity Management:
Third Line
 Systemic medications are effective, but
often have systemic side effects:
–
–
–
–
–
Hepatotoxicity (Baclofen, Dantrium)
Generalized weakness (Dantrium)
Lethargy (Zanaflex, Baclofen, Valium)
Hypotension (Zanaflex)
Addiction (Valium)
Spasticity Management:
Third Line
 Dantrolene Sodium (Dantrium)
– Acts peripheral by blocking release of Ca++ from the ttubules of the sarcoplasmic reticulum.
– Hepatotoxicity is not uncommon.
– May cause generalized weakness.
– No central effects.
– Most often used in Brain Injury and CVA.
– Start 25 mg qid -> Max 100 mg qid.
Spasticity Management:
Third Line
 Tizanidine (Zanaflex)
– Central acting alpha-blocker.
– Often causes hypotension.
– May cause lethargy.
– very gradual dose increase.
– Most often used in SCI.
– Start 1 mg tid -> Max 8 mg tid.
Spasticity Management:
Fourth Line
 Phenol (1-10% Aqueous Solution)
– Direct neurocidal agent, effect lasts for 3-6
months (until nerve regenerates). Works
immediately.
– Eliminates spasticity in specific nerve
distribution or muscle.
– Nerve/muscle motor point (where nerve
innervates) must be isolated electrically.
– Inexpensive.
Spasticity Management:
Fourth Line
 Botulinum Toxin (Botox, NeuroTox)
– Neurotoxin that prevents the release of
acetylcholine (Ach) from presynaptic vacuoles
at the neuromuscular junction.
– Produces paralysis of the muscle for 2-4
months.
– Maximal effects take 2 weeks.
– Expensive.
Spasticity Management:
Fourth Line
 Focal blockade needs to be combined with a
structured stretching/bracing program.
 Focal blockade often reveals underlying
connective tissue contractures.
– If they are “soft”, they can be improved with
stretching.
– If they are hard, surgical intervention is
indicated.
Guidelines for Medication
Usage After TBI
 Define the problem as objectively and specifically
as possible.
 Use medicines that have some proven efficacy;
don’t just use “something” (e.g. Neurontin).
 Develop clear cut goals and metrics to assist in
determining when to stop treatment.
 Begin low but get to a therapeutic dosing before
abandoning usage.
 Be alert to side effects and undesired effects.