ACMT Visual Pearl: If the Glove Fits

4. Phenytoin

Background

The image above depicts purple glove syndrome, an uncommon complication of intravenous phenytoin administration [1]. Phenytoin is an anticonvulsant drug that has been used in the treatment of epilepsy for decades. It is a sodium channel antagonist that prolongs the neuronal refractory period and likely has other mechanisms of action, including effects on calcium channels, glutamate, and GABA [2].

What is Purple Glove Syndrome?

One of the most concerning side effects of phenytoin administration is edema and poor perfusion to distal extremities, which leads to discoloration and ischemia, known as purple glove syndrome (PGS) [3,4]. PGS has a reported incidence of 1.7% – 5.9% [4]. It has also been reported less commonly after fosphenytoin administration [5].

Risk factors include: [3-7]

• Patients > 60 years old
• Female sex
• Peripheral vascular disease
• Multiple doses of phenytoin

What causes Purple Glove Syndrome? [1,4-8]

• The cause of PGS remains unclear.
• One proposed mechanism is that phenytoin and its diluent, propylene glycol, can induce thrombosis and vasoconstriction, which may lead to extravasation.
  • However, not all episodes of PGS involve obvious extravasation.
• Another is that phenytoin induces vasoconstriction, which disrupts the endothelial-intercellular junction, causing leakage of phenytoin into surrounding tissue. The drug then precipitates upon mixing with blood, leading to further irritation of the soft tissue.
• Another proposed mechanism is that the product’s high pH may lead to necrosis and disruption of the endothelium.
• There are also reports of oral phenytoin causing PGS, which would not involve the above-proposed mechanisms [5,9].

How does Purple Glove Syndrome present? [5-8]

• Stage 1: ~ 2 – 12 hours post infusion: blue-purple discoloration at the IV site
• Stage 2: ~ 12 – 24 hours post infusion: discoloration spreads to surrounding tissue, development of edema and/or blistering
• Stage 3: Improvement of swelling and discoloration localizes back to the original site and resolves

Rarely, PGS can progress to compartment syndrome, necrosis, and vascular compression, resulting in the need for debridement, skin grafting, and/or amputation [5-7,10].

How can we reduce the likelihood of Purple Glove Syndrome? [5-8,10,11]

• Use > 20-gauge IV needle & large vein.
• Dilute only with normal saline (NS) to prevent precipitation.
• Although PGS may not be a rate-related phenomenon, follow the recommended infusion rate, which should not exceed 25 mg/min in the elderly or those with poor peripheral perfusion.
• Flush IV site after administration with NS.
• Consider oral dosing instead of IV dosing, however PGS has been reported with oral dosing [5,9].

How is Purple Glove Syndrome treated? [4-8]

• Management involves stopping the infusion, removal of the IV at the injury site, and supportive care, which may include:
  • Compressive dressings
  • Massage of the affected area
  • Warm and dry compresses, not cold, which can lead to vasoconstriction
  • Elevation of limb
• Watch closely for ischemic complications
• Resolution of skin findings can vary from days to weeks, but pain can last for months.

Bedside Pearls

• PGS is a rare but serious complication of phenytoin administration.
• Risk factors for PGS include age > 60, female sex, peripheral vascular disease, and multiple doses of IV phenytoin.
• Important ways to decrease the risk of PGS include using 20 gauge or larger IVs, dilution with NS, and flushing with NS following administration.
• If able, use oral phenytoin over IV phenytoin or consider fosphenytoin. However, be aware that PGS has been reported rarely with both oral phenytoin and fosphenytoin.
• If PGS occurs, stop infusion immediately, remove the IV, ensure limb elevation, and perform frequent neurovascular checks.