Presentation on theme: "Appropriate Medication Usage After TBI: Cognition, Behavior and Beyond"— Presentation transcript:
1Appropriate Medication Usage After TBI: Cognition, Behavior and Beyond David X. Cifu, M.D.The Herman J. Flax, M.D. Professor and ChairmanDepartment of Physical Medicine and RehabilitationVirginia Commonwealth University/Medical College of Virginia
2Guidelines 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.
3Alterations in Cognition and Behavior After TBI HypoarousalHypoattentionMemory DeficitsDepressionDeliriumAgitation
4Factors Affecting Cognitive and Behavioral Function After TBI Effects of the TBIMedical InstabilityInfectionMetabolic DisturbancesHormonal/NeuroEndocrine DisturbancesHypoxiaSleep-Wake DisturbancesPainSeizures
5Factors Affecting Cognitive and Behavioral Function After TBI MedicationsCognitive-Impairing MedicationsCentral 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)
6Factors Affecting Cognitive and Behavioral Function After TBI Cognitive-Improving MedicationsStimulants [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]
7Coma InterventionDirected Multisensory Stimulation (DMS) demonstrated superior (increased responsiveness, improved RLAS, improved GCS) versus Non-Directed Stimulation (NDS) in RLAS II patientsHall:Brain Injury 1992:6:435-45
8Coma InterventionComatose receiving greater therapy intensity (by 60%) demonstrated a 31% decrease in length of stay.Blackerby:Brain Injury 1989;4:167-73
9Cognitive 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
10Cognitive 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
11Methylphenidate (Ritalin) Modes of ActionRelease of Dopamine from reserpine sensitive presynaptic poolBraestrup: J Pharm. Pharmacol. 1977, 29:Inhibition of Dopamine uptakeFerris,Tang: J of Pharmacol. Exp. Ther. 1979, 210:Inhibition of Monoamine OxidaseSzporny, Gorog: Biochem. Pharmacol. 1961, 8:
12Methylphenidate (Ritalin) PharmacokineticsPeak serum levels are reached within 2 hours (Half life = 2-4 hrs)Both a wide inter-individual and intra-individual variability in serum concentrations existMPH levels are not different in responders and non-respondersGualtieri, CT, et al. J of Amer Acad of Child Psych 1982, 21(1):
13Selective Serotonin Re-Uptake Inhibitors (SSRI’s) Prozac, Zoloft, Paxil, CelexaInhibit CNS reuptake of SerotoninActivating antidepressants, however somnolence present w/ Paxil at doses >20 mg/dayIncrease dosage q 4-6 weeksIf treating depression, need to commit to 12 month course (or increase recurrence)
14Bromocriptine (Parlodel) Dopamine receptor agonistAdjunctive treatment for Parkinson’s diseaseSuggested for low level patients, however limited proven efficacyDosage: mg/day in 2 dosesIncrease dosage weeklyHigh incidence of N/V and Headaches with increasing dosages.
15Amantadine (Symmetrel) Potentiates Dopamine (mechanism unclear)Adjunctive treatment for Parkinson’s disease (tremor)Dosage: mg/day in bid dosing (elevated seizure risk above 300 mg/day)Increase dosage weeklyHallucinations dose limiting side effect.Probable efficacy in RLAS III patients.
16Other Antidepressants [Effexor, Wellbutrin] Effexor and Wellbutrin inhibit Serotonin, NE, and Dopamine reuptake = Activating agentsEffexor Dosage: mg/day in 2-3 doses (Occasional HTN side effects)Wellbutrin Dosage: mg/day in 3 doses (May have worsening effects on agitation)
17Levodopa-Carbidopa [Sinemet] Increases cerebral dopamineSuggested for low level patients, however limited proven efficacySide effects can include dyskinesias and cognitive changesDosage: mg Levodopa/day in 2-3 doses (tablets contain either 100 or 200 mg Levodopa)
18Anti-Alzheimer's Agents [Aricept, Exelon] Reversible cholinesterase inhibitors = increases cerebral acetylcholineEffective in improving memory in individuals with Alzheimer’s diseaseLimited research suggests efficacy in TBI patientsExtremely expensive, occasional GI side effects
19Treatment Algorithm: Hypoarousal/Hypoattention Day 1Define pathology -> CT/MRI, Mechanism of Injury, Secondary BIAssess function: DRS, FIM, RLAS (limited efficacy in RLAS I-III)Assess medical status -> Infections, Oxygenation, Metabolics, Fluid Status, SeizuresRemove medications -> H2 blockers, narcotics, central acting anti-HTN/GI, Benzodiazepines, SleepersDay 1-4Stabilize/Improve medical statusAssess/Improve sleep-wake cycle: Trazadone, AmbienAssess behavior: ABS, Therapy attendance/participation, Attention to Task
20Treatment Algorithm: Hypoarousal/Hypoattention Day 5-10Initiate Methylphenidate 5 mg q 7 am and 12 pm, increase 5-10 mg/day to 60 mg maximumMonitor behavior and sleep-wake cycleDay 10-20If Methylphenidate effective, continue at lowest effective dose for 2-3 weeks, then wean off in 2-4 daysIf 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).
21Cognitive 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
23Cognitive Interventions: Agitation TreatmentAssess for correctable etiologySleep/Wake ChartingMedical ManagementBehavioralestablish desired behaviorpositive reinforcementshapingstructured therapyAgitated Behavior ScaleAssess pattern of agitationDocumentationEvaluate effectiveness of interventionPhysical RestraintPharmacologicABS > 28ABS score 21 or higher objectively quantifies agitation. Occurs in 20-50% after brain injury.Note that Pharmacologic intervention is listed last. “Medical Management” implies pain control and correction of metabolic abnormalities.Trazodone and Ambien are first-line agents. Dose Trazodone in 50mg increments up to 300mg in single dose.Avoid benzodiazepines, Benadryl, and tricyclics.
24Agitation: Medications Day 1-3 Use prn for ABS >28AtivanRisperidoneDay 4+Schedule agents if persistent ABS > 28Aggression - 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:
25Post-Traumatic Seizures: Background TBI-related seizures account for 20% of symptomatic epilepsy. Hauser: Epilepsia 1991:32;429-45PTS accounts for 5% of all cases of epilepsy.Hauser: Epilepsia 1991:32;429-45Late PTS is present in 4-7% all TBI, nearly 20% rehab TBI, and 35-50% penetrating TBI patients.Yablon: Arch PM&R 1993:74;EEG has no predictive value for PTS Yablon: Arch PM&R 1993:74;
26Prophylaxis for PTS73% 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;No benefit to use of up to 1 month VPA.Temkin: J NeuroSurg 1999:91;AANS and AAPM&R recommend 7 days of either PTH or CBZ post-TBI.
27Prophylaxis for PTSDo 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.
28GI Ulcer ProphylaxisUse 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.
29GI Ulcer ProphylaxisNewer 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.
30Spasticity 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.
31Spasticity 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)
32Spasticity Management: Third Line Dantrolene Sodium (Dantrium)Acts peripheral by blocking release of Ca++ from the t-tubules 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.
33Spasticity 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.
34Spasticity 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.
35Spasticity 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.
36Spasticity 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.
37Guidelines 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.