Pharmacotherapy of Traumatic Brain Injury (TBI) 5378.pdf

summarized form of Acute brain injury from DIPIRO’S
PHARMACOTHERAPY A PATHOPHYSIOLOGIC APPROACH 12TH EDITION

1. Pharmacotherapy of
Acute Brain Injury
•Leta Yezachow Etena (4
th
year student Bachelor
of Pharmacy at wallaga university)

[email protected]

2. Contents
❖ Introduction
❖ Epidemiology
❖ Diagnosis
❖Clinical presentation
❖Treatment
❖Monitoring and Evalution

3. 1. Introduction
•A Traumatic Brain Injury (TBI) is typically the result of a sudden jolt or blow to the head, causing
the brain to hit against the skull.
•It disrupts normal brain function and can range from mild to severe.
•TBI can be classified based on severity ranging frommild traumatic brain injuryto severe
traumatic brain injury.[the job experience long-term cognitive, physical, or emotional
impairments|)

4. 2. Epidemiology
•Approximately 2.87 million persons sustain a TBI each year in the United States equating to
one occurring nearly every 11 seconds.
•Over 288,000 individuals require hospitalization each year.
•Over 56,000 deaths occur annually due to TBI.
•An estimated 5.3 million Americans live with disabilities resulting from TBI.
•Direct and indirect spending on hospitalized TBI patients reached $76.5 billion in 2010.
•Leading Cause: Falls are the leading cause of unintentional TBI (48%).
•TBI-related hospitalizations and deaths vary by age.
•Falls are the leading cause of death in individuals 65 years and older, while motor vehicle crashes are the
leading cause of death in those aged 15 to 34 and adults over 75.

5. 3. Primary Injury and Secondary Injury.
•Primary Injury:
•Cause: Direct impact of external force on the brain.
•Mechanism: Transfer of kinetic energy to brain structures (neurons,
synapses, glial cells, axons, and blood vessels).
•Types:
•Focal: Localized damage, such as contusions (bruises) and
•hematomas (blood clots).
•Diffuse: Widespread damage, often involving shearing or
•stretching forces, primarily affecting axons (diffuse axonal injury).
•Examples: Blunt force trauma, penetrating injuries,
acceleration/deceleration forces.
•Outcome: Immediate neurological damage, depending on the severity
of the injury.

6. •Secondary Injury:
•Cause: A cascade of events triggered by the primary injury, occurring
minutes, hours, or days after the initial impact.
•Mechanism: Disruption of the delicate balance between oxygen supply and
demand in the brain, leading to a metabolic crisis.
•Key Pathophysiologic Event: Cerebral ischemia (lack of blood flow to the brain).
•Factors contributing to Secondary Injury:
•Cerebral edema: Swelling of brain tissue, caused by damage to
blood vessels and cell walls.
•Expanding mass lesions: Hematoma growth, further compressing brain tissue.
•Cerebral vasospasm: Narrowing of blood vessels, reducing blood flow.
•Loss of vasoregulatory control: Inability of blood vessels to adjust blood flow
to meet the brain's needs.
•Hypoxemia: Low blood oxygen levels, often due to respiratory failure.
•Increased metabolic demand: Increased energy needs due to seizures,
agitation, or fever.

7. •Consequences to secondary :-
•Energy-independent cellular necrosis: Cell death characterized by membrane
lysis, edema, and inflammation.
•Energy-independent apoptosis: Programmed cell death, leading to cell
shrinkage and membrane dissolution.
•Calcium influx and accumulation: Leads to mitochondrial dysfunction,
inhibition of cellular respiration, and activation of destructive enzymes.
•Inflammation: Involves inflammatory mediators and nitric oxide, potentially
causing further damage.

8. Schematic illustration of the cascade of biochemical events proposed to occur following severe neurotrauma (secondary brain
injury). (Ca, calcium; Cl, chloride; CNS, central nervous system; K, potassium; Mg, magnesium; Na, sodium; PMN,
polymorphonucleocyte; PGH 2, prostaglandin H2, PGG 2 , prostaglandin PGG 2 PGI 2 prostaglandin PGI 2
.

9. 4. The Glasgow Coma Scale (GCS)
•GCS is a widely used system to assess the level of consciousness in patients
with brain injuries. It evaluates three key areas:
•Eye Opening: This assesses how the patient's eyes respond to stimuli.
The score ranges from 1 (no response) to 4 (spontaneous eye opening).
•Best Motor Response: This measures the patient's motor response to
stimuli. The score ranges from 1 (no response) to 6 (obeying commands).
•Best Verbal Response: This evaluates the patient's ability to
communicate verbally. The score ranges from 1 (no response) to 5
(oriented and converses)
•Interpretation
•Severe Brain Injury: GCS score of 3 to 8
•Moderate Brain Injury: GCS score of 9 to 12
•Mild or Minor Brain Injury: GCS score of 13 to 15
•.

11. •Other Diagnostic Tests:
•CT scan of the head: This is crucial for detecting mass lesions (e.g., hematomas) and structural signs of edema
(e.g., midline shift, compressed ventricles)
•Important Considerations:
•Ethanol or substance intoxication: These can affect the neurological examination and should be considered
when assessing the patient's GCS score.
•Hypotension, hypoxia, postictal state, hypoglycemia, electrolyte imbalances, or hypothermia: These factors
can also alter the neurologic examination.
•Opiates, sedatives, and neuromuscular blockers: These medications can affect the neurological
examination and should not be administered until the initial assessment is complete, if possible.

12. 5. Clinical Presentation
General:
•Level of consciousness: This is assessed using the Glasgow Coma Scale (GCS), which scores eye opening,
motor response, and verbal response.
•Mental status: A rapid deterioration in mental status strongly suggests an expanding lesion within the skull.
Symptoms:
•Posttraumatic amnesia: This refers to a period of time after the injury that the patient cannot recall. A duration
greater than 1 hour may indicate more severe injury.
•Dizziness: Increasing dizziness can be a sign of a more serious injury.
•Headache: A moderate-to-severe headache is a common symptom.
•Nausea/vomiting: These symptoms can occur due to increased intracranial pressure.
•Limb weakness: This may indicate damage to the brain or spinal cord.
•Paresthesia: A tingling or numbness sensation may occur due to nerve damage.

13. •Signs:
•Cerebrospinal fluid (CSF) otorrhea or rhinorrhea: This indicates a leak of CSF from the ear or nose,
respectively, and suggests a skull fracture.
•Seizures: These can occur shortly after the injury or days later.
•Unequal or unreactive pupils: This may indicate pressure on the brainstem.
•Abnormal breathing patterns: These can include apnea (cessation of breathing), Cheyne-Stokes
respiration (alternating periods of deep and shallow breathing), and tachypnea (rapid breathing).
•Hypertension or bradycardia: These vital sign changes can occur due to increased intracranial pressure.
•Laboratory Tests:
•Arterial blood gases (ABGs): These can reveal hypoxia (low oxygen levels) or hypercapnia (high carbon
dioxide levels), indicating ventilation problems.
•Blood ethanol concentration and/or urine toxicology results: These can help determine if substance
intoxication is contributing to the patient's mental status.
•Electrolyte disturbances: These can affect mental status and interfere with the neurological assessment.

14. 6. TREATMENT

15. Goal of treatment
➢Establishment of an adequate airway and maintenance of ventilation and circulation
during the initial period of resuscitation and evaluation,
➢Maintenance of balance between CDO and CMRO
➢Prevention or attenuation of secondary neuronal injury
➢Prevention and/or treatment of associated medical complications.

18. Pharmacologic Therapy
•Focuses on establishing an adequate airway, maintaining ventilation and circulation, and preventing aspiration.
•Airway:Ensure an open airway to facilitate adequate oxygenation.
•Blood Pressure:Correct and prevent early hypotension (goal SBP >100 mm Hg for pt ages 50 to 69 years or >110
mm Hg for pt ages 15 to 49 or over 70 years).
•Fluids:Isotonic saline (0.9% normal saline) and lactated Ringer’s solution are traditionally used as initial
resuscitation fluids. There's no clear consensus on the optimal initial resuscitation fluid, and lower volumes of
crystalloids may be associated with improved survival.
•Vasopressors:If hypotension persists after adequate volume restoration, vasopressors and inotropic agents may be
needed to maintain an adequate mean arterial pressure (MAP).
•Nonpharmacologic Management of Intracranial Hypertension:
•Head of Bed:Elevate the head of the bed 30°.
•Ventricular Drainage:If an extraventricular drain (EVD) is present, use ventricular drainage.
Initial Resuscitation

19. •Following successful resuscitation, priorities shift toward diagnostic evaluation of
intracranial and extracranial injuries, and emergent surgical intervention as needed.
•1. Emergent Surgical Interventions:
•Evacuation of Intracranial Hematomas:Removing blood clots (epidural, subdural, intracerebral
hematomas) is crucial to reduce ICP and improve outcomes.
•Elevation of Depressed Skull Fractures:These fractures can compress the brain and require
surgical correction.
•Debridement of Penetrating Wound Tracts:Surgical removal of foreign objects and damaged
tissue is necessary for penetrating injuries.
•Decompressive Craniectomies:This procedure involves removing a portion of the skull to
relieve pressure on the brain. It's considered for patients with refractory ICP, but its
effectiveness and long-term consequences remain controversial.
Postresuscitative Care

20. •2. Intracranial Pressure (ICP) Monitoring and Management:
•Continuous ICP Monitoring:Traditionally, this has been the mainstay of ICP management using
extraventricular drains (EVDs) or intraparenchymal fiberoptic catheters.
•BTF/AANS Guidelines:Recent guidelines have softened the recommendations for routine ICP monitoring,
suggesting that invasive monitoring may not be superior to clinical/radiologic assessment.
•ICP Treatment Goal:If continuous ICP monitoring is employed, the goal is to treat any ICP values above 22
mm Hg (2.9 kPa), as higher values are associated with increased mortality.
•Multimodality Neuromonitoring (MMM):This approach uses advanced technologies like cerebral
microdialysis, CBF, brain tissue oxygenation, EEG, and transcranial Doppler (TCD) monitoring to assess
various cerebral parameters. However, its use is limited due to the complexity and availability of these
technologies.
•Jugular Venous Oxygen Saturation Monitoring:BTF/AANS guidelines recommend considering this
advanced monitoring modality to improve outcomes in TBI patients.
•Biochemical Markers:Markers like S-100 calcium-binding protein B, neuron-specific enolase, and glial
fibrillary acidic protein may have utility in diagnosing and monitoring TBI, but their roles are still being
defined.
Postresuscitative Care

21. •3. Cerebral Perfusion Pressure (CPP) Management:
•CPP Calculation:CPP is the difference between mean arterial pressure (MAP) and ICP (CPP = MAP - ICP).
•CPP Goal:BTF/AANS guidelines recommend maintaining a CPP range between 60 and 70 mm Hg (8.0 and 9.3 kPa). Aggressive
attempts to maintain CPP greater than 70 mm Hg (9.3 kPa) in adults should be avoided due to the risk of acute respiratory distress
syndrome.
•CPP Management Strategies:
•Fluid Management:Euvolemia (normal blood volume) is the goal to avoid hypoosmolar states and negative fluid
balance.
•Packed Red Blood Cell (PRBC) Transfusion:Indicated if hemoglobin is below 7 g/dL (70 g/L; 4.34 mmol/L).
Liberal transfusions should be avoided.
•Vasopressors:Used to increase MAP if fluid resuscitation is insufficient. Monitor for renal dysfunction, lactic
acidosis, and peripheral ischemia.
•Head Elevation:Elevating the head by 30° promotes venous drainage and decreases ICP.
Postresuscitative Care

22. •Pain, agitation, and excessive muscle movement can lead to transient increases in ICP
•Medications in controlling pain, agitation, and excessive muscle movement, which can exacerbate
ICP.
•Sedation and Analgesia:These medications help reduce pain, agitation, and muscle activity, thereby
minimizing ICP fluctuations.
•Paralytics:Used as a secondary option in refractory cases or during stimulatory procedures to
further reduce ICP.
•Morphine Sulfate:Most commonly used analgesic and sedative, but bolus doses may increase ICP
by increasing cerebral blood flow (CBF).
•Fentanyl and Sufentanil:Gaining popularity, but may be associated with mild elevations in ICP.
Anesthetics, Analgesics, and Sedatives

23. •Propofol:
•Sedative of choice for many clinicians due to ease of titration, rapid reversibility, and possible
neuroprotective effects.
•Concerns include propofol infusion syndrome (PRIS) and potential neurotoxicity characterized by
hyperkalemia, hepatomegaly, lipemia, metabolic acidosis, myocardial failure, rhabdomyolysis,renal failure, and death in
some cases
•Triglyceride concentrations also should be monitored in patients receiving prolonged propofol infusions and/or
high dosages considering its lipid emulsion formulation and the potential for inducing hypertriglyceridemia
under these conditions.
•Benzodiazepines (Midazolam):Useful for alcohol withdrawal-related agitation.
•Pentobarbital, Ketamine, Dexmedetomidine, Etomidate:Alternative sedatives, but
potential for decreasing MAP and CPP must be monitored.
Anesthetics, Analgesics, and Sedatives

24. •High-Dose Barbiturate Therapy (Barbiturate Coma):
•MOA;- suppress cerebral metabolism, reducing cerebral metabolic demands and CBV, thereby lowering ICP.
•Indications:Considered in hemodynamically stable patients with severe TBI refractory to maximal medical ICP-lowering
therapy and decompressive surgery.
•Administration:Pentobarbital is the most common agent, administered as a loading infusion followed by maintenance
infusion.
•Monitoring:Continuous monitoring of arterial blood pressure, ECG, and ICP is essential.
•Goals:Maintain ICP and CPP at target thresholds and achieve EEG burst suppression.
•Withdrawal:Tapered over 24-72 hours to prevent ICP spikes.
•Adverse Effects:
•Hypotension:Common with barbiturates, requiring dose reduction or blood pressure support.
•Gastrointestinal Effects:Decreased GI tone and contraction, followed by hypermotility on emergence from coma.
•Tissue Damage:Extravasation of barbiturate solutions can cause severe tissue damage.
•Hepatic Metabolism:Barbiturates can induce hepatic medication metabolism, affecting other medications.
•Neurologic Examination:Barbiturates can interfere with neurologic examination.
•Contraindications:Prophylactic use is not advocated due to insufficient evidence and potential for adverse
events (hypotension).
Anesthetics, Analgesics, and Sedatives

25. •Effective in preventing or reducing cerebral edema in patients with non-traumatic conditions that
produce vasogenic edema.
•In moderate-to-severe TBI
•Use of corticosteroids in TBI is not supported by current evidence due to they are associated with
increased mortality and complications
•However, studies in TBI patients have not shown that corticosteroids lower intracranial pressure
(ICP) or improve outcomes.
•Adverse Effects
•Complications including:
•Gastrointestinal (GI) bleeding
•Glucose intolerance
•Electrolyte abnormalities
•Infection
Corticosteroids

26. •While conventional treatments have significantly reduced morbidity and mortality in
TBI, the need for neuroprotective agents remains crucial.
•These agents aim to target specific pathophysiological processes that contribute to
secondary brain injury, such as ischemia, hypoxia, and increased ICP
•Calcium Antagonists:Modulating calcium influx to protect neurons.
•Glutamate Antagonists (e.g., Magnesium):Blocking excitotoxicity.
•Antioxidants/Free Radical Scavengers:Combating oxidative stress.
•Inhibitors of Inflammatory Mediators:Reducing inflammation.
•3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors
(statins):May have neuroprotective effects.
•Sympatholytics:May reduce the stress response and improve outcomes.
Investigational Therapy

27. •Adult patients experiencing one or more seizures after moderate-to-severe TBI should receive antiseizure medication therapy.
•to prevent increases in cerebral metabolic rate of oxygen (CMRO2) associated with seizures and to avoid the development of status epilepticus, which carries a high
mortality risk.
•Initial Therapy: Active seizures are terminated with IV diazepam or lorazepam, followed by IV phenytoin to prevent recurrence.
•Phenytoin Dosing: A loading dose of 15-20 mg/kg for adults and 10-15 mg/kg for children is followed by a maintenance dose of 5 mg/kg/day.
Fosphenytoin, a water-soluble form, can be used as an alternative.
•Prophylactic Therapy: The use of prophylactic antiseizure medication in patients without a post-injury seizure is debated. Risk factors for early
posttraumatic seizures (within 7 days) include a GCS score < 10, cortical contusion, depressed skull fracture, hematomas, penetrating head wound,
or seizures within the first 24 hours.
•Valproate: Not recommended due to a trend towards higher mortality compared to phenytoin.
•Levetiracetam: A potentially attractive option, but large randomized clinical trials are lacking. Meta-analyses suggest similar efficacy to
phenytoin with a potentially better safety profile. It has become the antiseizure medication of choice in some European neurotrauma
centers.
Posttraumatic Seizures

28. •This text focuses on the importance of supportive care in TBI patients, beyond just managing intracranial pressure (ICP) and cerebral
perfusion pressure (CPP).
• It emphasizes the need to address systemic and extracranial complications to improve overall outcomes.
•Systemic Hypertension: Treated with antihypertensives like labetalol, nicardipine, and enaliprilat.
•Fluid and Electrolyte Management: Aggressive monitoring and treatment of electrolyte disturbances (hyponatremia,
hypomagnesemia, hypokalemia, hypophosphatemia).
•Nutritional Support: Early feeding (within 7 days) is associated with better outcomes, with early enteral nutrition showing
particular benefits.
•Hyperglycemia: Intensive insulin therapy is not recommended due to potential adverse effects on brain glucose metabolism.
Conventional glucose control is preferred.
•Infectious Complications: Aggressive treatment of nosocomial pneumonia, sepsis, urinary tract infections, and meningitis,
with careful attention to antibiotic blood-brain barrier penetration.
•Hyperthermia: Avoidance of hyperthermia, as it is associated with poorer outcomes. Maintaining a core temperature below
37.5°C is crucial.
Supportive Care

29. •Acute gastritis prophylaxis
•Prevention of decubiti and contractures
•Thromboembolic Event Prevention:
•Intermittent pneumatic compression devices (preferred) or graduated compression stockings initially.
•Pharmacological prophylaxis (low-molecular-weight heparin or unfractionated heparin) based on individual risk factors.
•Initiation of prophylaxis within 24-48 hours post-injury for patients with minor bleeding or good ICP control.
•Prophylaxis within 72 hours post-injury for patients at moderate-to-high risk of intracranial hemorrhage.
•Prophylaxis continued until patients are ambulatory.
•Caution with systemic anticoagulation in patients with severe intracerebral hemorrhage or those requiring early craniotomy.
•Coagulopathy Management:
•Monitoring for coagulopathy, as it is common and associated with increased ICU length of stay and mortality.
•Low platelet count is a strong predictor of intracranial bleeding progression.
•Tranexamic acid is a less expensive alternative to recombinant factor VIIa for reversing coagulopathy.
•Tranexamic acid within 3 hours of injury in patients with GCS > 3 has shown a significant decrease in mortality in a large
randomized trial (CRASH-3).
•The mortality benefit of tranexamic acid may be more pronounced in mild-to-moderate TBI.
Supportive Care

31. Evaluation of Therapeutic Outcomes

32. Thank you for reading