What drugs cause purple glove syndrome and how to prevent it?

October 8, 2025 •

4 min read

Intravenous (IV) administration of phenytoin, an anti-seizure medication, is the overwhelmingly primary cause of a rare and potentially serious adverse reaction known as purple glove syndrome (PGS). Affecting anywhere from 1.7% to 5.9% of patients receiving IV phenytoin, this condition can cause severe pain, swelling, and discoloration of the hand and forearm.

Quick Summary

Purple glove syndrome is primarily linked to intravenous phenytoin due to its high alkalinity and poor solubility, which can cause tissue irritation and damage. Understanding the risk factors and proper administration techniques is critical for prevention, with alternative medications available.

Key Points

Phenytoin is the Primary Cause: Intravenous phenytoin is the main medication associated with causing purple glove syndrome due to its highly alkaline solution and poor water solubility.
Extravasation is a Key Factor: The condition is often linked to the extravasation (leakage) of the phenytoin solution into the soft tissues around the IV site, causing irritation, vasoconstriction, and potential crystal precipitation.
Fosphenytoin is a Safer Alternative: The prodrug fosphenytoin was developed as a safer alternative to IV phenytoin, as its neutral pH and high water solubility eliminate the risk of purple glove syndrome.
Risk Factors Increase Vulnerability: Advanced age, using smaller hand veins, rapid infusion rates, and pre-existing vascular disease are known risk factors for developing purple glove syndrome.
Management is Supportive: Treatment involves immediately stopping the infusion, elevating the affected limb, applying warm compresses, and providing pain management; severe cases may require surgical intervention.
Prevention is the Best Strategy: Adhering to strict infusion guidelines for IV phenytoin or opting for the alternative fosphenytoin can effectively prevent this serious adverse reaction.

The Primary Culprit: Intravenous Phenytoin

The most significant and well-documented drug associated with purple glove syndrome (PGS) is intravenous (IV) phenytoin. Phenytoin is a long-standing anticonvulsant used to treat seizures and status epilepticus. While effective, its formulation for IV delivery is complex and creates the ideal conditions for PGS to occur. Phenytoin is not very soluble in water, so it requires special solvents, including propylene glycol and ethanol, and a highly alkaline pH of around 12 to remain in solution.

When this highly alkaline solution is infused into a patient's peripheral vein, it can cause significant irritation to the surrounding soft tissues, especially if it leaks out of the vein, a process called extravasation. Even without obvious signs of extravasation, the irritating nature of the solution can cause microvascular damage and leakage into the interstitial space. One theory suggests that the alkaline phenytoin solution, when mixed with the neutral pH of the blood, can precipitate and cause microvascular obstruction. This combination of chemical irritation, vasoconstriction, and potential precipitation is believed to be the root cause of PGS.

The Role of Alternative Drugs: Fosphenytoin

While phenytoin is the primary cause, the development of purple glove syndrome led to the creation of a safer alternative. Fosphenytoin is a pro-drug of phenytoin that was developed to circumvent the formulation problems of IV phenytoin.

Fosphenytoin vs. Phenytoin for PGS Risk


Feature	IV Phenytoin	IV Fosphenytoin
Vehicle	Propylene glycol, ethanol, high pH (alkaline)	Water-soluble vehicle with neutral pH (physiologic)
Mechanism of PGS	Chemical irritation, extravasation, vasoconstriction, potential precipitation	Minimizes risk due to better solubility and neutral pH
Incidence of PGS	Relatively rare but notable (1.7–5.9%)	No reported cases of PGS associated with fosphenytoin
Infusion Rate	Restricted to slow rates (≤50 mg/min) to prevent complications	Faster infusion rates are tolerated, reducing infusion time
Route of Administration	Peripheral IV is a major risk factor	Considered safer for peripheral IV administration

Because fosphenytoin is highly soluble at a neutral pH, it is far less caustic to the surrounding tissues. It is rapidly converted to phenytoin in the body, achieving the same therapeutic effect without the high risk of soft tissue injury. This superior safety profile is why fosphenytoin is often the preferred choice over IV phenytoin, especially in patients with a high risk of developing PGS. There are no documented cases of PGS being caused by fosphenytoin.

Less Common Instances and Risk Factors

While most cases are tied to the IV route, some reports have suggested a link to oral phenytoin administration, although this is extremely rare. In these cases, the exact mechanism is less clear but may relate to a systemic effect rather than local tissue irritation.

Several risk factors heighten a patient's vulnerability to PGS when receiving IV phenytoin:

Elderly patients: Older age is a significant risk factor, likely due to more fragile veins.
High or frequent doses: Larger and more frequent administrations of IV phenytoin increase the risk.
Location of IV: Use of smaller peripheral veins, such as those in the hand, increases the likelihood of extravasation and irritation.
Rapid infusion rates: Exceeding the recommended infusion rate of 50 mg/min is a major risk factor.
Coexisting conditions: Patients with pre-existing vascular disease, sepsis, or other chronic debilitating illnesses are more susceptible.

How to Prevent Purple Glove Syndrome

Preventing this adverse event is crucial and relies on a combination of best practices and drug selection. Healthcare providers should adhere to the following guidelines:

Use Fosphenytoin: For patients requiring parenteral phenytoin, consider using fosphenytoin, which carries a significantly lower risk of PGS.
Follow Infusion Protocols: Always administer IV phenytoin at a slow, controlled rate, typically not exceeding 50 mg/min. Some advocate for even slower rates (e.g., 20 mg/min) for high-risk patients.
Proper Dilution: Dilute IV phenytoin only in 0.9% saline and administer it immediately after mixing to prevent precipitation. Do not use dextrose solutions.
Monitor IV Site: Carefully monitor the IV site for any signs of pain, swelling, or discoloration during and after the infusion.
Consider Central Lines: For patients requiring prolonged or frequent IV phenytoin, a central venous catheter should be considered to minimize the risk of peripheral extravasation.

Conclusion

Purple glove syndrome is a rare but serious complication almost exclusively associated with the intravenous administration of phenytoin. The high alkalinity and poor solubility of the IV phenytoin formulation make it a significant irritant, capable of causing painful tissue damage and discoloration, often related to extravasation. Recognition of the symptoms and immediate cessation of the drug are critical for managing the condition and preventing severe outcomes. However, the most effective strategy is prevention through careful administration and, most importantly, the preferential use of fosphenytoin, a safer and more soluble alternative. By being aware of what drugs cause purple glove syndrome and implementing preventative measures, healthcare professionals can significantly reduce the risk of this adverse reaction for their patients.(https://www.cureus.com/articles/86761-purple-glove-syndrome-recognizing-a-rare-complication-of-intravenous-phenytoin)

Frequently Asked Questions

Purple glove syndrome (PGS) is a rare but serious adverse reaction characterized by severe pain, edema, and a purplish or bluish discoloration of the limb, typically affecting the hand and forearm, following the intravenous administration of phenytoin.

The IV formulation of phenytoin is highly alkaline and poorly soluble in water, requiring caustic excipients like propylene glycol and ethanol. This irritates and damages the blood vessels and surrounding tissue, especially if the solution leaks (extravasates) from the vein.

While the vast majority of cases are caused by the intravenous route, there have been a few isolated case reports suggesting that oral phenytoin could also lead to purple glove syndrome, although this is extremely rare.

Yes, fosphenytoin is considered a safer alternative to IV phenytoin concerning purple glove syndrome. As a pro-drug with a neutral pH and high solubility, it is much less irritating to the tissues and has no reported cases of causing PGS.

Symptoms of purple glove syndrome typically appear within 2 to 12 hours after the intravenous infusion of phenytoin. They progress over the next 12 to 24 hours, with edema and discoloration spreading distally from the injection site.

Management involves immediate cessation of the phenytoin infusion, elevating the affected limb, applying dry, warm compresses, and providing supportive pain management. In severe cases with necrosis, surgical interventions like fasciotomy or debridement may be required.

Prevention includes using fosphenytoin when possible, adhering to slow infusion rates for IV phenytoin (≤50 mg/min), proper dilution with saline, careful site monitoring, and considering central venous access for high-risk patients.