I. Overview of Escalating Pharmacotherapy

Acute ischemic stroke (AIS) demands rapid reperfusion strategies while meticulously balancing hemorrhagic risks. The overarching pharmacotherapy plan aims not only to address the acute event but also to set the stage for effective secondary prevention.

Goals of Therapy:

• Restore cerebral blood flow (reperfusion) to the ischemic penumbra.
• Minimize the risk of hemorrhagic transformation of the infarct.
• Facilitate neurologic recovery and prevent early and long-term stroke recurrence.

Escalation Framework:

1. Intravenous (IV) fibrinolysis (alteplase or tenecteplase) for eligible patients.
2. Adjunctive antiplatelet therapy, timed appropriately post-fibrinolysis or initiated early if fibrinolytics are contraindicated.
3. Mechanical thrombectomy consideration for large vessel occlusion (LVO), often in conjunction with or following IV fibrinolysis.
4. Implementation of secondary prevention agents and comprehensive supportive care.

II. Intravenous Fibrinolytics

A. Agent Selection

• Alteplase: A fibrin-specific plasminogen activator. It remains the standard of care for eligible patients presenting within 3 hours of symptom onset, with an extended window to 4.5 hours for select patient populations.
• Tenecteplase: Exhibits higher fibrin specificity and a longer half-life compared to alteplase, allowing for single-bolus dosing (0.25 mg/kg). It is an emerging off-label option, particularly for patients eligible for mechanical thrombectomy.

B. Dosing and Administration

Infusion Setup Considerations (primarily for Alteplase):

• Utilize a dedicated IV line. Confirm Y-site compatibility if other infusions are necessary.
• Central venous access is preferred if peripheral venous access is inadequate or multiple concurrent critical infusions are running.
• Ensure thorough line flush with normal saline before and after drug administration to guarantee delivery of the full dose.

C. Contraindications and Monitoring

Absolute Exclusions for Fibrinolysis:

• Evidence of active internal bleeding.
• History of recent intracranial hemorrhage or intracranial/intraspinal surgery.
• Known intracranial neoplasm, arteriovenous malformation, or aneurysm.
• Uncontrolled blood pressure persistently >185/110 mmHg despite acute antihypertensive therapy.

Relative Exclusions (requiring careful risk-benefit assessment):

• Minor or rapidly improving, non-disabling stroke symptoms.
• Recent major surgery or serious trauma (within 14 days).
• Age >80 years (particularly for the extended 3-4.5 hour window).

Blood Pressure Management:

Early Warning Signs of Complications:

• Acute neurological deterioration (suggesting hemorrhagic transformation or infarct extension).
• Severe headache, acute hypertension, nausea, or vomiting.
• Orolingual angioedema (a rare but serious complication, more common with ACE inhibitor use).

III. Adjunctive Antiplatelet Therapy

Post-fibrinolysis, antiplatelet therapy plays a crucial role in reducing the risk of early recurrent ischemic events. However, timing is critical to minimize bleeding complications.

• Standard Post-Fibrinolysis: Aspirin (initial dose 160–325 mg) should generally be initiated 24–48 hours after IV fibrinolytic administration, but only after follow-up imaging (typically non-contrast CT) has excluded intracranial hemorrhage.
• For Patients Ineligible for Fibrinolysis: Aspirin should be initiated as soon as possible once intracranial hemorrhage has been ruled out by imaging.
• Dual Antiplatelet Therapy (DAPT): For patients with minor, non-cardioembolic ischemic stroke (e.g., NIHSS score ≤3) or high-risk TIA, DAPT with aspirin and clopidogrel, started within 24 hours of symptom onset and continued for 21 days, may be beneficial. This is typically for patients not receiving fibrinolytics.

IV. Pharmacokinetic/Pharmacodynamic (PK/PD) Adjustments in the Critically Ill

Critical illness can introduce physiological changes that may alter drug behavior, although specific dose adjustments for AIS therapies based solely on critical illness status are not routinely made.

• Volume of Distribution (Vd): Conditions like capillary leak syndrome or significant edema, common in some critically ill patients, can increase the Vd of hydrophilic drugs. This might theoretically lower peak concentrations, but clinical impact on fibrinolytics is not well-defined.
• Protein Binding: Hypoalbuminemia, frequently seen in critical illness, can increase the free fraction of highly protein-bound drugs (e.g., some antiplatelet agents or adjunctive medications). This could potentially enhance their effect or toxicity.
• Blood-Brain Barrier (BBB) Disruption: Ischemic stroke itself disrupts the BBB. Critical illness might further exacerbate this, potentially altering CNS penetration of drugs, though this is complex and drug-specific.

V. Dosing in Organ Dysfunction

The impact of organ dysfunction on fibrinolytic and antiplatelet therapy in AIS requires careful consideration, primarily focusing on safety.

• Renal Impairment & Renal Replacement Therapies (RRT):
  • Alteplase and tenecteplase are primarily cleared via hepatic metabolism, not renal excretion.
  • Continuous Renal Replacement Therapies (CRRT) and intermittent hemodialysis (HD) are unlikely to significantly affect the clearance of these large protein molecules.
  • Therefore, no specific dose reductions for fibrinolytics are recommended in patients with renal impairment or those on RRT. However, uremia-associated platelet dysfunction can increase bleeding risk, warranting heightened vigilance.
• Hepatic Impairment:
  • Since fibrinolytics are metabolized in the liver, severe hepatic impairment could theoretically slow drug metabolism and prolong their effects, potentially increasing bleeding risk.
  • However, guideline-specified dose adjustments are not provided. Clinical judgment and careful monitoring for bleeding are paramount in patients with significant liver disease. Coagulopathy associated with liver failure is a relative or absolute contraindication to fibrinolysis.

VI. Administration Routes and Devices

Proper administration techniques are vital for the safety and efficacy of AIS pharmacotherapies.

• Alteplase Infusion:
  • Must be administered using a programmable infusion pump to ensure accurate delivery of the calculated dose over 60 minutes after the initial bolus.
  • A dedicated IV lumen is strongly recommended to prevent inadvertent mixing with incompatible drugs or interruption of the infusion.
  • Confirm line compatibility and flush thoroughly before and after administration.
• Tenecteplase Bolus:
  • Administered as a single IV bolus over approximately 5-10 seconds. This simplifies delivery significantly compared to alteplase.
  • Reduces the need for infusion pumps and dedicated lines for the fibrinolytic itself, potentially decreasing resource burden and nursing time.
• General Considerations:
  • Strict adherence to Y-site compatibility checks is mandatory if multiple IV medications are required.
  • Line-flushing protocols (e.g., with 0.9% sodium chloride) before and after administration of any IV push or infusion medication are essential to ensure the complete dose is delivered and to prevent drug interactions within the IV tubing.

VII. Monitoring Plan

A comprehensive monitoring plan is essential to detect complications early and assess treatment response.

Neurological Examinations:

• Perform NIH Stroke Scale (NIHSS) assessment at baseline (pre-treatment).
• Repeat NIHSS at frequent intervals post-treatment: typically at 2 hours, then at 24 hours, and with any change in neurological status. Some protocols include hourly checks for the first few hours.

Vital Signs:

• Blood pressure and heart rate: Every 15 minutes during alteplase infusion and for the first 2 hours post-infusion.
• Then, every 30 minutes for the next 6 hours.
• Then, hourly until 24 hours after treatment initiation.
• Temperature, respiratory rate, and oxygen saturation as per institutional stroke protocol.

Imaging:

• Non-contrast head CT or MRI at 24 hours post-fibrinolysis (before initiating antiplatelets or anticoagulants).
• Urgent imaging for any sudden neurological deterioration, severe headache, or suspicion of intracranial hemorrhage.

Laboratory Tests:

• Baseline: Complete blood count (CBC) with platelet count, coagulation profile (PT/INR, aPTT), glucose.
• Repeat labs (especially CBC, coagulation) if bleeding is suspected or occurs.

VIII. Pharmacoeconomic Analysis

The choice of fibrinolytic agent can have pharmacoeconomic implications, particularly when comparing alteplase and tenecteplase.

• Drug Acquisition Costs:
  • While variable, tenecteplase (0.25 mg/kg dose for stroke) may often be less expensive per typical treatment course compared to alteplase, especially considering weight-based dosing and vial sizes.
  • Alteplase often requires multiple vials for a single patient, which can increase waste if partial vials are used.
• Resource Utilization:
  • Tenecteplase: Its single-bolus administration significantly reduces nursing time associated with infusion setup, monitoring during infusion, and pump management. It also eliminates the need for dedicated infusion pumps for the fibrinolytic itself.
  • Alteplase: Requires an infusion pump, dedicated IV line for an hour, and more intensive nursing monitoring during the infusion period.
• Overall Impact:
  • High-volume stroke centers, particularly those performing mechanical thrombectomy (where tenecteplase is increasingly used), may realize notable cost savings and improved workflow efficiencies with the adoption of tenecteplase.
  • Reduced preparation and administration time for tenecteplase can also contribute to faster door-to-needle times.

A comprehensive pharmacoeconomic analysis should also consider the costs associated with managing complications (e.g., hemorrhage), length of stay, and long-term disability, though direct comparisons based on these broader outcomes are still evolving.

IX. Clinical Algorithm and Case Illustration

The management of AIS follows a time-sensitive, protocol-driven approach. The following algorithm outlines key decision points in escalating pharmacotherapy: