Extravasation occurs when a vesicant or irritant drug inadvertently leaks from a blood vessel into the surrounding tissue, causing local inflammation, pain, and potentially serious tissue damage. Some extravasated substances, such as hyperosmolar agents, chemotherapeutic agents, and contrast media, can cause necrosis if left untreated.

Hyaluronidase, an enzyme that depolymerizes hyaluronic acid in the extracellular matrix, is used to enhance drug dispersion and absorption, making it an effective treatment for extravasation. This article provides a comprehensive, evidence-based review of the role of hyaluronidase in extravasation management, including mechanisms, indications, dosage, administration protocol, efficacy, safety profile, and best practices.

Understanding Extravasation and Its Consequences

Definition and Causes of Extravasation

Extravasation refers to the leakage of intravenously administered medications or fluids into surrounding tissues due to:

• Vessel wall damage (e.g., puncture, trauma).
• Inappropriate catheter placement (e.g., dislodgment).
• Increased infusion pressure (e.g., rapid infusion of viscous drugs).

Types of Extravasated Agents

Extravasated substances can be categorized based on their potential for tissue damage.

Consequences of Extravasation

• Local inflammation (pain, erythema, swelling).
• Tissue necrosis (in severe cases).
• Fibrosis and scarring, leading to functional impairment.
• Infections and secondary complications.

Early intervention is critical to minimize tissue damage and long-term consequences.

Role of Hyaluronidase in Extravasation Management

Hyaluronidase is an enzyme that hydrolyzes hyaluronic acid, which is a key component of the extracellular matrix. By breaking down hyaluronic acid, hyaluronidase increases tissue permeability, facilitating the absorption and dispersal of extravasated substances.

Mechanism of Action

• Reduces interstitial viscosity, allowing the extravasated drug to disperse more rapidly.
• Enhances systemic absorption, decreasing local toxicity.
• Increases capillary permeability, improving drug clearance.

Indications for Hyaluronidase Use in Extravasation

Hyaluronidase is most effective in the treatment of extravasation from non-chemotherapeutic vesicants and irritants, including:

• Hyperosmolar agents (e.g., total parenteral nutrition, mannitol).
• Parenteral medications (e.g., phenytoin, nafcillin, contrast media).
• Local anesthetics (e.g., lidocaine, bupivacaine).
• Parenteral nutrition solutions (e.g., dextrose >10%).

For chemotherapy extravasation, hyaluronidase is effective for certain agents (e.g., vinca alkaloids) but not recommended for others (e.g., anthracyclines, which require specific antidotes such as dexrazoxane).

Recommendation Products

Hyaluronidase Extravasation Management Protocol

Immediate Steps for Any Extravasation

1. Stop Infusion Immediately: Prevent further leakage of the drug.

2. Do Not Remove the IV Catheter: This allows for potential administration of an antidote (e.g., hyaluronidase).

3. Aspirate Any Residual Drug: Using a syringe, attempt to withdraw any extravasated fluid.

4. Mark the Affected Area: Outline the margins with a skin marker to monitor progression.

5. Elevate the Limb: Helps reduce swelling and promotes drainage.

6. Apply Warm or Cold Compress (Depending on the Drug)

• Warm compress (for hyaluronidase-sensitive agents like vinca alkaloids) promotes dispersion.
• Cold compress (for cytotoxic drugs like anthracyclines) limits tissue damage.

Hyaluronidase Administration Protocol

1. Dilution and Preparation: Dilute the hyaluronidase according to the product instructions. In general, the recommended dilution is 150 units in 1 mL of normal saline. Some protocols use a concentration of 15-75 units per mL, depending on the severity of extravasation.

2. Injection Method: Subcutaneous (SC) or intradermal (ID) injection is performed according to the product instructions, strictly following the dosage per site and needle gauge as indicated in the instructions. In general, inject in a radial pattern around the extravasation site, at 5-10 sites for even distribution. Avoid injecting directly into the extravasation pocket.

3. Timing and Frequency: Ideally administered within 1-2 hours of extravasation. A single dose is often sufficient, but in severe cases repeat dosing (every 6-12 hours) may be considered.

4. Post-Treatment Monitoring: Observe the patient for 24-48 hours for signs of improvement while continuing limb elevation and symptomatic treatment as needed. If symptoms persist, consult a specialist, such as a plastic surgeon.

Safety Profile and Contraindications

Potential Side Effects

• Mild erythema and swelling (transient, resolves within hours).
• Hypersensitivity reactions (rare, mostly in bovine-derived formulations).
• Pain or discomfort at the injection site.

Contraindications

• Allergy to hyaluronidase (perform a skin test if history of allergic reactions is unclear).
• Concurrent use with certain chemotherapeutic agents (e.g., anthracyclines).
• Infected or inflamed tissue sites (increases the risk of infection spread).

Case Studies

Case 1: Hyaluronidase for the Management of Dextrose Extravasation; Wiegand and Brown, 2009

In this study, a 17-year-old girl experienced extravasation after receiving a dextrose 50% water injection in the antecubital region, resulting in erythema and swelling. While most extravasations are mild, severe cases can cause long-term damage and may require surgical intervention. Hyaluronidase, an enzyme traditionally derived from bovine tissue, is used to enhance drug absorption and manage extravasation of certain irritants. Although it is not FDA approved for dextrose extravasation, it has shown benefit with hyperosmolar substances. In this case, hyaluronidase was injected into multiple sites, resulting in resolution of symptoms with no complications at follow-up. The study suggests hyaluronidase as a potential treatment for dextrose and other extravasations.

Case 2: Management of Amiodarone Extravasation with Intradermal Hyaluronidase; Fox et al., 2017

This study demonstrated that a 60-year-old man with multiple injuries from a motor vehicle collision developed atrial fibrillation postoperatively and was started on intravenous amiodarone. On postoperative day 6, he experienced amiodarone extravasation in his left arm, resulting in severe pain and an expanding area of induration. Initial treatment included warm compresses and elevation of the limb, but due to persistent pain, the medical team administered intradermal hyaluronidase. This intervention resulted in significant pain relief and reduced erythema with no adverse effects. The patient was discharged to inpatient rehabilitation on postoperative day 10, highlighting hyaluronidase as a potential treatment for amiodarone extravasation.

Hyaluronidase as a First-Line Treatment for Extravasation

Hyaluronidase is a highly effective and safe intervention for the extravasation of hyperosmolar drugs, contrast media, and vinca alkaloids. Its ability to improve drug distribution, reduce local toxicity and prevent long-term complications makes it a valuable tool in clinical practice.

Key takeaways

• Administer as early as possible for best results (within 1-2 hours).
• Use a dilution of 150 units per mL and inject subcutaneously around the site of extravasation.
• Monitor patients for 24-48 hours with repeat dosing as needed.

Creative Enzymes offers high-quality, high-performance hyaluronidase products for research and industrial applications. Contact us today for more information.