Neurology 111 Traumatic brain injury Pharmacotherapy

Lesson 5, Topic 7

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Pharmacotherapy

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Initial Management

Rapid Sequence Intubation (RSI) in TBI

Rapid Sequence Intubation (RSI) is a critical procedure in the initial management of patients with severe injuries, including traumatic brain injury (TBI), and is especially indicated in patients with a Glasgow Coma Scale (GCS) score of 8 or below. RSI is essential for ensuring airway protection and respiratory support in patients with severe extracranial injuries, agitation, intoxication, or those at risk for declining mental status.

Key Pharmacotherapy Considerations in RSI:

Choice of Induction Agents: The selection of appropriate induction agents for RSI is crucial. While some agents like propofol can significantly lower blood pressure, others such as etomidate or ketamine are often more suitable choices due to their relatively stable hemodynamic profile.
Pre-oxygenation and Oxygen Saturation Maintenance: Prior to intubation, patients must be pre-oxygenated with 100% oxygen to ensure adequate oxygen saturation (SaO2 > 90%). This step is vital to prevent hypoxemia during the procedure.
Monitoring and Capnography: Along with standard pulse oximetry and electrocardiography (ECG) monitoring, capnography is highly beneficial in guiding cerebral resuscitation. Capnography measures the concentration of carbon dioxide (CO2) in exhaled breath, providing real-time feedback on the patient’s respiratory status. However, it is important to note that capnography might underestimate the actual partial pressure of arterial carbon dioxide (paCO2), especially in critically ill patients or those with low cardiac output.

Induction Agents

Etomidate
- Mechanism of Action: Etomidate acts as a GABA_A receptor agonist. It enhances the effects of GABA, a major inhibitory neurotransmitter in the brain.
- Dosing: Typically, a dose of 0.3 mg/kg is administered intravenously.
- Advantages: Preferred for hemodynamically unstable patients due to minimal cardiovascular effects. Rapid onset and short duration.
- Side Effects: Adrenal suppression, myoclonus, nausea, vomiting.
- Clinical Pearls: Avoid in septic patients due to adrenal suppression. Rapid recovery profile makes it ideal for short procedures.
Propofol
- Mechanism of Action: Propofol enhances GABA_A receptor activity, causing sedation, hypnosis, and decreased cerebral metabolic demand.
- Dosing: 1-2 mg/kg IV is a common induction dose.
- Advantages: Rapid onset and short duration of action. Provides significant cerebral protection by decreasing cerebral blood flow.
- Side Effects: Hypotension, respiratory depression, pain on injection.
- Clinical Pearls: Use cautiously in hypovolemic or hemodynamically unstable patients due to profound hypotensive effects.
  1. Reduces ICP and cerebral metabolic rate but can cause significant hypotension, especially in hypovolemic patients.
Ketamine
- Mechanism of Action: NMDA receptor antagonist, providing dissociative anesthesia and analgesia.
- Dosing: 1-2 mg/kg IV for induction.
- Advantages: Preserves airway reflexes and respiratory drive, increases heart rate and blood pressure.
- Side Effects: Emergence reactions (hallucinations), increased salivation
- Clinical Pearls:
  1. Traditionally avoided in TBI due to concerns about increasing intracranial pressure (ICP). However, recent evidence suggests it does not significantly increase ICP and can be used safely, especially when hemodynamic stability is a concern.
  2. Provides analgesia and amnesia without significant respiratory depression.
  3. Sympathomimetic properties can increase blood pressure and heart rate, potentially beneficial in hypotensive TBI patients.

Midazolam
- Mechanism of Action: Benzodiazepine that enhances GABA_A receptor activity.
- Dosing: 0.2-0.3 mg/kg IV for induction.
- Advantages: Anxiolysis, anterograde amnesia, muscle relaxation.
- Side Effects: Respiratory depression, hypotension, paradoxical reactions.
- Clinical Pearls: Use with caution in elderly or hemodynamically unstable patients.
  1. Used less frequently due to its longer onset of action and duration.

Paralytics

Succinylcholine
- Mechanism of Action: Depolarizing neuromuscular blocker. It binds to nicotinic acetylcholine receptors causing muscle fasciculations followed by paralysis.
- Dosing: 1-2 mg/kg IV.
- Advantages: Rapid onset (45-60 seconds), short duration (5-10 minutes).
- Side Effects: Hyperkalemia, malignant hyperthermia, increased intraocular pressure, bradycardia.
- Clinical Pearls: Contraindicated in burn, crush injuries, denervating diseases, and hyperkalemia. Ideal for rapid control of airway.
  1. Can cause a transient increase in ICP, so caution is advised in TBI patients
Rocuronium
- Mechanism of Action: Non-depolarizing neuromuscular blocker. Competes with acetylcholine for nicotinic receptors at the neuromuscular junction.
- Dosing: 1-1.2 mg/kg IV for rapid sequence induction.
- Advantages: No significant cardiovascular effects, no increase in intracranial pressure.
- Side Effects: Prolonged paralysis, especially in renal failure.
- Clinical Pearls: Alternative to succinylcholine, especially in patients at risk for hyperkalemia. Duration of action is dose-dependent.
  1. Does not increase ICP
  2. Larger dose >1 mg/kg could lead to prolonged duration up to 3-4 hours
Vecuronium
- Mechanism of Action: Non-depolarizing neuromuscular blocker similar to rocuronium.
- Dosing: 0.1 mg/kg IV.
- Advantages: Intermediate duration of action, minimal cardiovascular effects.
- Side Effects: Prolonged neuromuscular blockade in renal and hepatic impairment.
- Clinical Pearls: Use in situations where intermediate duration of paralysis is desired. Requires careful monitoring of neuromuscular function.

Table: RSI Medication in Traumatic Brain Injury (TBI)

Induction Agents

Drug	Mechanism of Action	Dosing	Advantages	Side Effects	Clinical Pearls
Etomidate	GABA_A receptor agonist	0.3 mg/kg IV	Minimal cardiovascular effects, rapid onset, short duration	Adrenal suppression, myoclonus	Avoid in septic patients; ideal for short procedures
Propofol	Enhances GABA_A receptor activity	1-2 mg/kg IV	Rapid onset, decreases cerebral blood flow, cerebral protection	Hypotension, respiratory depression	Use cautiously in hypovolemic patients
Ketamine	NMDA receptor antagonist	1-2 mg/kg IV	Preserves airway reflexes, increases heart rate and blood pressure	Emergence reactions, old data says increased ICP	Can be used in TBI, beneficial in hypotensive patients
Midazolam	Benzodiazepine, enhances GABA_A receptor activity	0.2-0.3 mg/kg IV	Anxiolysis, anterograde amnesia, muscle relaxation	Respiratory depression, hypotension	Use with caution in elderly or unstable patients; longer onset and duration

Drug	Mechanism of Action	Dosing	Advantages	Side Effects	Clinical Pearls
Succinylcholine	Depolarizing neuromuscular blocker	1-2 mg/kg IV	Rapid onset, short duration	Hyperkalemia, malignant hyperthermia	Contraindicated in certain conditions; transient ICP increase in TBI patients
Rocuronium	Non-depolarizing neuromuscular blocker	1-1.2 mg/kg IV	No cardiovascular effects, no ICP increase	Prolonged paralysis	Alternative to succinylcholine, dose-dependent duration
Vecuronium	Non-depolarizing neuromuscular blocker similar to rocuronium	0.1 mg/kg IV	Intermediate duration, minimal cardiovascular effects	Prolonged blockade in renal/hepatic impairment	Suitable for intermediate duration paralysis, requires neuromuscular monitoring

Hemodynamic Management

Hemodynamic management in patients with traumatic brain injury (TBI) is a crucial aspect of care, primarily focused on maintaining adequate cerebral perfusion and preventing secondary brain injury caused by hypotension and hypoxemia. This management is critical from the pre-hospital setting through to intensive care.

Initial Resuscitation

Volume resuscitation with isotonic fluids is recommended as first-line therapy for hypotension. Balanced crystalloids are preferred, normal saline is acceptable
- goal fluid administration rate for adults: 1-2 L in the first hour to achieve target blood pressure

Vasopressors

If fluid resuscitation fails to restore blood pressure, vasopressors should be used
First line:
- norepinephrine, dopamine, phenylephrine
vasopressin may be considered as an adjunct in vasodilatory shock

Considerations for vasopressor choice

norepinephrine: most effective at increasing MAP with little effect on HR or cardiac output
dopamine: tends to increase HR and may worsen tachycardia
phenylephrine: pure α-agonist which increases MAP with reflexive bradycardia

Dosing

start with low dose (e.g. norepinephrine 0.05 mcg/kg/min)
titrate to lowest dose necessary to achieve MAP goal

Monitoring

continuous monitoring of BP and cardiac rhythm
monitor urine output, peripheral perfusion

Blood Pressure Goals

Adults

Maintain SBP at a minimum of 100 mmHg.
For patients aged 15–49 years or >70 years, the goal is SBP > 110 mmHg.
Mortality improvements may not correlate with a single threshold and are inversely related to SBP across a range (40–119 mmHg).

Pediatrics

Infants:
- Systolic blood pressure minimum 60 mmHg
Toddlers (1-3 years):
- Systolic blood pressure minimum 70 + (2 x age in years) mmHg
Older children (4-17 years):
- target MAP is 50 + (2 x age in years) mmHg
For example, a 15 year old should have MAP 72 mmHg as target.

Titrate based on ICP response (if monitored) and signs of adequate vs. inadequate cerebral perfusion across all age groups.

The optimal target blood pressure to minimize secondary ischemic injury while avoiding complications of vasopressor therapy is not known and requires individualized assessment. More aggressive targets may be utilized (e.g. MAP >80-90 mmHg) if hypotension and cerebral hypoperfusion persist despite initial hemodynamic support.

Duration of BP Support

Aim to wean vasopressors over 24-48 hours as tolerated while ensuring adequate BP and CPP. Extended courses of vasopressors may increase risk of complications [tissue necrosis, limb ischemia, SIRs].

Consider Red Blood Cell Transfusion

May be utilized as temporizing measure in setting of active hemorrhage or pre-existing anemia – target Hb 7-9 g/dL. Ensure adequate blood product availability and correct coagulopathies prior to transfusion.

Cerebral Perfusion Pressure (CPP) Maintenance

CPP Goals:
- The target CPP is approximately 60–70 mmHg.
- In children, a CPP of 45–60 mmHg is targeted, with infants at the lower end and older children and teenagers at the upper end.
- After appropriate resuscitation, vasopressor administration may be necessary to maintain cerebral perfusion.
- Vasopressors should not be used to augment CPP above 70 mmHg.
- Red blood cell (RBC) transfusion can be considered for anemic or actively bleeding patients.

Clinical Implications

For Pharmacists and Healthcare Professionals:
- Awareness of the importance of maintaining appropriate SBP and CPP in TBI patients.
- Understanding the role of fluid type in resuscitation, particularly the use of normal saline and hypertonic saline.
- Recognizing the need for vasopressors in maintaining CPP post-resuscitation, while avoiding excessive CPP augmentation.

References for Hemodynamic Management

Antifibrinolytic Agents in the Management of Traumatic Brain Injury

Introduction to Antifibrinolytic Agents

Antifibrinolytic agents play a significant role in managing hemorrhage, a common and severe complication of traumatic brain injury (TBI). These agents work by inhibiting the breakdown of fibrin, thus stabilizing clots and reducing bleeding. In the context of TBI, their use is critical in controlling hemorrhage and preventing secondary brain injury due to bleeding.

Common Antifibrinolytic Agents Used in TBI

Tranexamic Acid (TXA):
- Mechanism of Action: TXA inhibits the conversion of plasminogen to plasmin, preventing the degradation of fibrin clots.
- Dosage and Administration:
  - The typical dosing regimen includes a loading dose followed by a maintenance infusion.
  - Loading Dose: 1 gram administered intravenously over 10 minutes.
  - Maintenance Dose: 1 gram infused over 8 hours.
Epsilon-aminocaproic Acid:
- Less commonly used but operates on a similar mechanism as TXA.

Clinical Evidence Supporting the Use in TBI

CRASH-2 and CRASH-3 Trials:
- CRASH-2 was a randomized, placebo-controlled trial that included over 20,000 trauma patients with or at risk of significant bleeding from various causes, including TBI. It showed that TXA reduced all-cause mortality by 1.5% (from 16% to 14.5%) and death due to bleeding by 0.8% (from 5.7% to 4.9%). The benefits of TXA were consistent across different subgroups of patients, regardless of injury severity, baseline systolic blood pressure, or time to treatment.
- CRASH-3 specifically demonstrated the importance of early administration of TXA.
  - CRASH-3 was a similar trial that focused on over 12,000 TBI patients with Glasgow Coma Scale (GCS) scores of 12 or less. It found that TXA reduced head injury-related death by 0.6% (from 18.5% to 17.9%) in the overall population, and by 2.1% (from 19.8% to 17.7%) in the subgroup of patients with mild to moderate TBI (GCS 9-12). There was no evidence of benefit in patients with severe TBI (GCS 3-8) or in patients treated more than three hours after injury. There was also no increase in adverse events such as seizures, stroke, or thromboembolism associated with TXA use.

Indications and Patient Selection

Timing of Administration:
- Early administration, ideally within the first three hours post-injury, is critical for effectiveness.
Patient Selection Criteria:
- Patients with confirmed or suspected TBI with signs of ongoing hemorrhage are prime candidates for antifibrinolytic therapy with best data in patients with GCS 9-12

Potential Benefits and Risks

Benefits:
- Reduced progression of intracranial hemorrhage and potentially improved survival.
Risks:
- While generally safe, there is a minimal risk of thromboembolic events.

Monitoring and Management

Monitoring Parameters:
- Continuous monitoring for signs of thromboembolic events or allergic reactions.
Management of Side Effects:
- Immediate medical intervention for any signs of adverse reactions.
Considerations for Different TBI Severities:
- Tailoring the use of antifibrinolytic agents based on the severity of TBI and the presence of other injuries.

Pharmacist’s Role in the Management

Clinical Counseling and Education:
- Pharmacists play a vital role in educating patients and caregivers about the importance of timely administration of antifibrinolytic agents.
Collaboration with Healthcare Team:
- Ensuring optimal patient care through collaboration with physicians, nurses, and other healthcare professionals.

Antifibrinolytic agents, particularly TXA, have emerged as a key component in the management of TBI. Their timely administration can significantly impact the outcomes of TBI patients, making them an essential element in the arsenal against TBI-related hemorrhage.

Intracranial Pressure (ICP) Management

Traumatic brain injury (TBI) is a common cause of elevated intracranial pressure (ICP), which can lead to secondary brain injury and poor outcomes. ICP management in TBI aims to prevent or treat increased ICP and maintain adequate cerebral perfusion pressure (CPP), which is the difference between mean arterial pressure (MAP) and ICP. CPP reflects the blood flow to the brain, and its optimal range depends on the patient’s cerebral autoregulation status. The main strategies for ICP management in TBI include non-pharmacologic and pharmacologic interventions, as well as surgical decompression in selected cases.

ICP Threshold

The threshold for initiating ICP management in TBI is >22 mm Hg, although individualized targets based on CPP and brain tissue oxygenation may be considered.

Table: Signs of Intracranial Pressure (ICP) Elevation

Sign of ICP Elevation	Description
Changes in Level of Consciousness	Confusion, restlessness, agitation, lethargy
Headache, Nausea, Vomiting, Blurred Vision	Symptoms often associated with increased ICP
Pupillary Changes	Unequal or dilated pupils, impaired pupillary light reflex
Motor Deficits	Hemiparesis, posturing, decerebrate or decorticate rigidity
Cushing’s Triad (Late Sign of Brain Herniation)	Hypertension, bradycardia, and irregular breathing
Pupillary Changes	Unequal or dilated pupils, impaired pupillary light reflex

This table provides an organized summary of the various signs associated with elevated intracranial pressure, which is crucial for accurate diagnosis and timely intervention in clinical settings.

Non-Pharmacologic Management

Positioning

Head of bed elevation: Elevate the head of the bed to 30-45 degrees to facilitate venous drainage and reduce ICP
Avoid neck flexion or rotation: These positions can impede jugular venous outflow and increase ICP
Keep the head in midline alignment: This position optimizes cerebral perfusion pressure and reduces the risk of ischemia

Surgical Management

Decompressive Craniectomy

This involves the removal of a portion of the skull to allow a swelling brain room to expand without being compressed.

Evacuation of Hematomas

Surgical intervention to remove space-occupying clots like subdural or epidural hematomas that contribute to increased ICP.

External ventricular drain (EVD)

An external ventricular drain (EVD) is commonly used to monitor and manage elevated ICP, allowing for direct measurement and drainage of cerebrospinal fluid to reduce pressure within the cranial vault.

Hyperventilation

Intracranial pressure (ICP) management in traumatic brain injury (TBI) often involves hyperventilation, a technique used to lower ICP by reducing cerebral blood flow. Hyperventilation is induced by increasing the patient’s ventilation rate, thereby decreasing arterial CO2 levels (PaCO2), which leads to cerebral vasoconstriction and subsequent ICP reduction.
Aim for a paCO2 of 28–35 mmHg or ETCO2 of 25–30 (20 breaths/min in an adult) for a brief time until you can apply a final treatment for brain herniation.

Hypothermia

Rationale
- Hypothermia in traumatic brain injury (TBI) is utilized to reduce metabolic demands and intracranial pressure, potentially offering neuroprotection. Clinical guidelines, however, recommend cautious application due to mixed evidence on outcomes and risks of complications.
Guideline Recommendation on Hypothermia:
- The Brain Trauma Foundation’s guidelines on the management of severe traumatic brain injury suggest that prophylactic hypothermia (cooling to 32-35°C) is not recommended to improve outcomes in patients with diffuse injury.

Osmotherapy

Definition and Overview: Osmotherapy refers to the use of osmotically active substances to reduce intracranial pressure (ICP) and cerebral edema in various clinical situations, particularly in the management of severe traumatic brain injury (TBI) and other neurological conditions.
Role in Clinical Practice: It plays a crucial role in neurocritical care by manipulating the osmotic gradient to draw fluid out of the brain tissue, thereby reducing ICP and mitigating secondary brain injury.

Mannitol

Mechanism of Action: Mannitol, an osmotic diuretic, works by increasing the osmolarity of blood, leading to a fluid shift from the brain tissue into intravascular spaces.
Indications and Usage in Clinical Settings: Commonly used in the treatment of elevated ICP and cerebral edema resulting from TBI, stroke, or brain tumors.
Dosing Guidelines: The typical dose ranges from 0.25 to 1 g/kg, administered intravenously, usually as a bolus over 10-20 minutes.
Pharmacokinetics: Rapid onset of action, generally within 10-15 minutes, with effects lasting up to 6 hours. It is predominantly excreted unchanged in the urine.
Potential Side Effects and Management: Includes dehydration, electrolyte imbalances (like hyponatremia), and renal dysfunction. These effects are managed through careful monitoring of fluid balance and renal function.
Monitoring and Adjustments: Regular monitoring of serum electrolytes, renal function, and osmolality is crucial. Dose adjustments may be necessary based on patient response and lab values.

Hypertonic Saline

Mechanism of Action: Increases serum osmolarity, creating an osmotic gradient that draws water from the brain tissue into the bloodstream, thus reducing ICP.
- Indications and Usage in Different Scenarios: Used in the management of severe TBI, hyponatremic encephalopathy, and other conditions associated with cerebral edema.
- Dosing & Administration
  - 3% Hypertonic Saline:
    - Adults: Initial dose typically ranges from 150-500 mL (or 3-5 ml/kg) over 20-30 minutes, followed by an option of continuous infusion at a rate of 0.1 to 1 mL/kg/hour.
    - Can generally be administered safely through a peripheral intravenous (IV) line
  - 23.4% Hypertonic Saline:
    - Adults: Typically used as a bolus for severe intracranial hypertension, with doses ranging from 30 to 60 mL over 5 to 10 minutes.
    - 23.4% NaCl can be administered through a large peripheral vein in an emergent situation
      - According to study published in Critical Care found that peripheral venous administration of 23.4% NaCl is safe and achieves a reduction in ICP equivalent to that achieved by administration via central venous access.
        Faiver, L., Hensler, D., Rush, S.C. et al. Safety and Efficacy of 23.4% Sodium Chloride Administered via Peripheral Venous Access for the Treatment of Cerebral Herniation and Intracranial Pressure Elevation. Neurocrit Care 35, 845–852 (2021).
- Adverse Effects and Their Management: Includes hypernatremia, dehydration, and potential renal impairment. Management involves close monitoring of serum sodium levels and overall fluid balance.
- Monitoring and Necessary Adjustments: Regular assessment of serum sodium, osmolality, and neurological status is essential. Dose adjustments should be made based on these parameters and clinical response.

Anesthetics, Analgesics, and Sedatives

Use of Analgesics and Sedatives

Purpose of Analgesics and Sedatives: the purpose of analgesia and sedation in TBI patients is to achieve optimal neuroprotection and neurologic recovery while minimizing adverse effects.
Analgesics in TBI: The use of analgesics in TBI patients must be approached cautiously. Non-opioid analgesics like acetaminophen are generally preferred for mild to moderate pain, as they have minimal impact on cerebral physiology. Opioids may be necessary for severe pain but should be used judiciously due to risks like respiratory depression and increased intracranial pressure (ICP). Continuous monitoring is essential when administering opioids to TBI patients.
Sedatives in TBI: Sedation in TBI patients is complex, as it can affect cerebral hemodynamics and ICP. Agents like propofol and dexmedetomidine are often used due to their short half-life and lower risk of lowering ICP. The choice of sedative should be individualized based on the patient’s neurologic status and overall medical condition.
Monitoring and Titration: Close monitoring of neurological status and ICP is crucial in TBI patients receiving analgesics and sedatives. The goal is to achieve adequate pain control and sedation while minimizing potential adverse effects on cerebral physiology. Titration of these medications should be done cautiously and in response to clinical and, if available, monitoring data (like ICP readings).
Impact on Patient Outcomes: The choice and management of analgesics and sedatives can significantly impact outcomes in TBI patients. Over-sedation can mask neurological changes, while under-sedation can lead to agitation and increased ICP. A balance must be maintained to optimize patient outcomes.

These considerations reflect the complex nature of managing TBI patients and underscore the need for careful selection and monitoring of analgesic and sedative therapy. Each patient’s unique clinical situation should guide therapy decisions.

High-Dose Barbiturate Therapy

Guideline Recommendation: Recommended to control elevated ICP refractory to maximum standard medical and surgical therapy (Level IIB)
Common Agents: Pentobarbital and Thiopental
Indication: Used in TBI for refractory intracranial hypertension (ICP > 20 mmHg) unresponsive to first-line treatments.
Dosing
- Pentobarbital:
  - Loading dose: 10 mg/kg IV over 30 minutes, then 5 mg/kg over 3 hours
  - Maintenance dose: 1-3 mg/kg/hr.
- Thiopental:
  - Loading dose: 3-5 mg/kg.
    - Maintenance dose: Variable, titrated to effect.

Anticoagulation Reversal

Warfarin Reversal:

Agent: Vitamin K, Prothrombin Complex Concentrates (PCCs), Fresh Frozen Plasma (FFP).
Indication: Reversal of Warfarin’s anticoagulant effect.
Vitamin K
- Vitamin K gives the vitamin K that activates vitamin K–dependent clotting factors by gamma-carboxylation. But vitamin K does not reverse quickly because clotting factors take 6-24 hours to make.
- Dosing: Vitamin K 5-10 mg intravenously
- Kinetics: Vitamin K requires 6-24 hours for synthesis of clotting factors.
Prothrombin Complex Concentrates (PCCs
- Dosing
  - Fixed dose
    - 1500 to 2000 international units
  - Variable dosing
    - 25 units/kg for INR 2 to 4; 35 units/kg for INR 4 to 6; and 50 units/kg for INR >6, with a maximum dose of 5000 units
Adverse Effects: Vitamin K does not provide immediate reversal. PCCs and FFP can rapidly correct INR.
Kinetics: PCCs can correct INR within 30 minutes.
Guideline Recommendation:
- The 2022 AHA/ASA guidelines give a strong recommendation for prompt warfarin reversal with intravenous vitamin K and 4-factor PCC over FFP in intracranial hemorrhage. This is supported by the INCH trial showing improved INR correction, reduced hematoma expansion, and lower mortality compared to FFP

DOAC Reversal:

Agents: Idarucizumab, Andexanet alfa, 4-factor PCC, Activated PCC (aPCC).
Indication: Reversal of anticoagulant effect of DOACs like dabigatran, apixaban, and rivaroxaban.
Dosing:
- Idarucizumab 5 grams IV For dabigatran
- Andexanet alfa varies based on DOAC
  - Apixaban: 400 mg bolus + 4 mg/min IV infusion x 120 minutes
  - Rivaroxaban: 800 mg bolus + 8 mg/min IV infusion x 120 minutes
- 4-factor PCC: 50 units/kg IV
Adverse Effects and Monitoring: Monitoring includes diluted thrombin time or ecarin clotting time for dabigatran, anti-factor Xa level for factor Xa inhibitors, and viscoelastic testing if available.
Guideline Recommendation
- The 2022 AHA/ASA guidelines recommend andexanet alfa with strong evidence if available for factor Xa reversal. If unavailable, 4-factor PCC or aPCC have conditional recommendations based largely on observational data.
- ACC expert consensus also endorses specific reversal agents like idarucizumab and andexanet alfa for DOAC reversal in serious bleeding. If unavailable, PCCs are suggested as an alternative based on low-quality evidence.

Heparin Reversal:

Agent: Protamine.
- Mechanism of action:
  - Cationic protein that binds to anionic heparin through an ionic interaction. This forms a stable complex to inhibit heparin’s anticoagulant effect.
- Indication: Reversal of unfractionated heparin’s anticoagulant effect.
- Dosing:
  - Unfractionated heparin: 1 mg protamine per 100 units heparin based on dose in prior 2-3 hours
  - Low molecular weight heparin: 1 mg protamine per 1 mg low molecular weight heparin based on prior 8-12 hour dose
  - Maximum single doses: 50 mg (unfractionated heparin), 30-50 mg (low molecular weight heparin)
Adverse Effects and Kinetics: Protamine effectively reverses unfractionated heparin; however, the optimal dosing for low molecular weight heparin reversal is uncertain.
Guideline Recommendation:
- NCC/SCCM2016 Guidelines
  - We recommend administering intravenous protamine sulfate to reverse heparin in the context of intracranial hemorrhage. (Strong recommendation, moderate quality evidence)

Antiplatelet Reversal

Agents and Mechanisms

Aspirin: Irreversibly inhibits cyclooxygenase (COX)-1 and COX-2 enzymes, leading to downstream inhibition of thromboxane A2.
Thienopyridines (e.g., Clopidogrel, Ticlopidine, Prasugrel): Irreversibly inhibit the P2Y12 receptor for adenosine diphosphate (ADP) on platelets, preventing ADP binding and platelet aggregation.
Ticagrelor and Cangrelor: Reversibly inhibit the ADP receptor.
Dipyridamole: Reversibly inhibits ADP uptake by platelets.

Controversies and Management

Controversy in Management: There is no consensus on how to manage patients on aspirin, clopidogrel, and other antiplatelet drugs.
Lack of Guidelines for Reversal: No clear guidelines exist for the reversal of antiplatelet agents.

Platelet Transfusion

In Vitro Model: Suggests that 2-3 units of platelets or 2-3 single-donor apheresis units added to plasma from healthy volunteers can normalize platelet function.
Clinical Evidence: The Platelet Transfusions for Intracerebral Hemorrhage (PATCH) trial found that platelet transfusion for spontaneous intracerebral hemorrhage (ICH) in patients on antiplatelet therapy did not reduce bleeding and led to increased mortality and dependence.

Desmopressin (DDAVP)

Mechanism: Increases endothelial release of von Willebrand factor (vWF) and factor VIII.
Usage: May be used to reverse the effects of aspirin and clopidogrel.
Clinical Efficacy: In elective or emergent cardiac surgery in patients on antiplatelet therapy or with measured platelet dysfunction, DDAVP use resulted in 25% less total volume of red blood cells transfused, 23% less blood loss, and a smaller risk of reoperation due to bleeding.
Adverse Effects: No decrease in mortality or increase in thrombotic events observed, but increased clinically significant hypotension reported.
Guidelines: Supported by the Neurocritical Care Society and Society of Critical Care Medicine for a one-time 0.4 micrograms per kilogram IV dose in patients with ICH on antiplatelet therapy.

Seizure Prophylaxis

Seizures are common in patients with TBI and can worsen the neurological outcome. Some guidelines recommend the following:

Use AEDs for the first seven days after severe TBI
Use levetiracetam or phenytoin as the preferred AEDs
Use AEDs only if there is evidence of intracranial hemorrhage, depressed skull fracture, or penetrating injury
Monitor the AED levels and adjust the dose as needed

Agents

Phenytoin
- Loading dose: 15-20 mg/kg IV, usually administered at a rate not exceeding 50 mg/min.
- Maintenance dose: Typically, 100 mg orally or IV three times daily, but the dose may be adjusted based on serum level monitoring and patient response.
Levetiracetam (Keppra)
- Loading dose: 1000 mg or 20 mg/kg IV or orally, administered once.
- Maintenance dose: 500-1000 mg orally or IV twice daily, with dose adjustments based on clinical response and tolerability.

Corticosteroids

Role of Corticosteroids in TBI: The use of corticosteroids in Traumatic Brain Injury (TBI) is controversial and lacks clear evidence of benefit.
Rationale for Use:
- Theoretical benefits include attenuation of secondary injury mechanisms post-TBI, such as cerebral edema, ischemia, oxidative stress, and excitotoxicity.
- Aim to reduce intracranial pressure (ICP) and improve cerebral perfusion pressure (CPP), potentially limiting neuronal damage and improving outcomes.
Clinical Evidence and Trials:
- CRASH (Corticosteroid Randomisation After Significant Head Injury) study: Found high-dose methylprednisolone increased mortality and disability in severe TBI.
- Cochrane review of 19 trials (over 10,000 patients): Concluded corticosteroids do not reduce death/disability risk post-TBI, and may be harmful.
Current Guidelines:
- Brain Trauma Foundation and European Federation of Neurological Societies: Recommend against routine corticosteroid use in TBI.

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