Mechanisms and treatment regimens for non-cytotoxic drug extravasations^[1-3]

Primary mechanism of injury	Drug	Other mechanism(s)	Toxicity	Compresses*	Potential antidote(s) for peripheral catheter extravasation
Acidic	Amiodarone	NI	Necrosis	Cold or warm	None
	Gentamicin	NI	Necrosis	Cold	None
	Metronidazole	NI	Necrosis, gangrene	Cold	None
	Nicardipine	NI	Necrosis	Cold	None
	Promethazine	NI	Necrosis	Cold or warm	None
	Vancomycin	NI	Necrosis	Warm if hyaluronidase used; cold may be used if hyaluronidase is not used	Hyaluronidase may be considered based on mechanism of injury^¶
Alkaline	Acyclovir	NI	Necrosis	Cold	None
	Aminophylline	Hyperosmotic	Ischemia	Cold	None
	Furosemide	NI	Necrosis	Cold	None
	Ganciclovir	NI	Necrosis	Cold	None
	Phenobarbital	NI	Necrosis	Cold	None
	Phenytoin	Hyperosmotic, precipitation	Necrosis, purple glove syndrome	Warm	Hyaluronidase^¶ or topical nitroglycerin^Δ may be considered based on mechanism of injury
Chemical	Amphotericin	NI	Phlebitis	Cold	None
	Digoxin	NI	Inflammation, apoptosis	Cold	None
	Foscarnet	NI	Phlebitis, arteritis	Cold	None
	Propofol	NI	Necrosis	Cold	None
Hyperosmotic (osmolarity >290 mOsm/L) tissue damage may resemble compartment syndrome	Contrast media, radiographic	Pressure effect of large volume	Pressure necrosis	Cold or as per radiologist	None
	Calcium solutions	Vasoconstriction, calcinosis	Necrosis, calcinosis	Warm if hyaluronidase used; cold may be used if hyaluronidase is not used	Hyaluronidase^¶ Severe forms of cutaneous calcinosis have been treated with sodium thiosulfate infusions, eg, once weekly for 3 weeks
	Dextrose ≥10%	NI	Necrosis	Warm if hyaluronidase used; cold may be used if hyaluronidase is not used
	Magnesium sulfate	NI	Necrosis	Warm if hyaluronidase used; cold may be used if hyaluronidase is not used	None
	Mannitol >5%	NI	Necrosis	Warm if hyaluronidase used; cold may be used if hyaluronidase is not used	Hyaluronidase^¶
	Nafcillin	NI	Necrosis	Warm if hyaluronidase used; cold may be used if hyaluronidase is not used	Hyaluronidase^¶
	Parenteral nutrition/amino acids solutions	Acidic	Necrosis	Warm if hyaluronidase used; cold may be used if hyaluronidase is not used	Hyaluronidase^¶
	Potassium chloride >40 mEq/L	NI	Necrosis	Warm if hyaluronidase used; cold may be used if hyaluronidase is not used	Hyaluronidase^¶
	Sodium bicarbonate	NI	Necrosis	Warm if hyaluronidase used; cold may be used if hyaluronidase is not used	Hyaluronidase^¶
	Sodium chloride >1%	NI	Necrosis	Warm if hyaluronidase used; cold may be used if hyaluronidase is not used	None
	Valproate sodium	NI	Necrosis	Warm if hyaluronidase used; cold may be used if hyaluronidase is not used	None
Vasoconstriction (causing local ischemia)	Dobutamine	NI	Necrosis	Warm	2% topical nitroglycerin ointment^Δ and/or terbutaline administered subcutaneously may be considered
	Dopamine	Acidic	Necrosis	Warm	Preferred: Phentolamine^◊ Alternative: 2% topical nitroglycerin ointment^Δ Terbutaline administered subcutaneously has been used if phentolamine is unavailable
	Epinephrine	Acidic	Necrosis	Warm
	Methylene blue	NI	Cellular toxicity	Warm
	Norepinephrine	Acidic	Necrosis	Warm
	Phenylephrine	Acidic	Necrosis	Warm
	Vasopressin	Acidic	Necrosis	Warm	None documented; 2% topical nitroglycerin ointment^Δ followed by phentolamine^◊ may be considered based on mechanism of injury

Recommendations are based on case descriptions, experience at some leading centers, or extrapolated according to mechanism of injury. Consult local protocols if available.
Antidotes listed are potential adjuncts to general extravasation injury care (ie, stop infusion immediately, do not flush line, leave catheter/needle in place to aspirate, elevate limb, evaluate as clinically indicated [eg, immediate surgery consultation]). Mild extravasations of small volume are generally amenable to supportive care and observation. Refer to topic discussion.

NI: none identified.

* Dry cold or warm compresses should be applied to affected area for 20 minutes once every 4 to 6 hours for 1 to 2 days after removal of the catheter/needle and limb elevation. Cold compresses reduce pain, inflammation, and localize the vesicant potentially facilitating administration of an antidote. Application of warmth causes vasodilation and may facilitate dispersion and absorption.

¶ Hyaluronidase, administered as multiple subcutaneous injections around affected area, enhances dispersion and absorption of extravasated medications. Ideally, administer within 1 hour of extravasation; some benefit may be derived within 12 hours. If hyaluronidase is used, avoid cold compresses as they oppose its action; warm compresses are preferred.

Δ Alternative, if phentolamine is unavailable, is topical nitroglycerin 2%, applied as 1 inch (2.5 cm) strip over affected area, should be applied within 1 hour of extravasation. Avoid use of warm compresses if topical nitroglycerin is used. Local injection of terbutaline has also been tried as an antidote for vasopressors if phentolamine is unavailable.

◊ Phentolamine, administered as multiple subcutaneous injections around affected area, antagonizes alpha-adrenergic receptors stimulated by catecholamine extravasation. Ideally administer as soon as possible; some benefit may be derived within 12 hours.

References:

David V, Christou N, Etienne P, et al. Extravasation of Noncytotoxic Drugs. Ann Pharmacother 2020; 54:804.
Le A, Patel S. Extravasation of noncytotoxic drugs: a review of the literature. Ann Pharmacother 2014; 48:870.
Reynolds PM, MacLaren R, Mueller SW, et al. Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy 2014; 34:617.

Adapted from: Valentin D, Christou N, Etienne P, et al. Extravasation of Noncytotoxic Drugs. Ann Pharmacother 2020; 54:804.

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Mechanisms and treatment regimens for non-cytotoxic drug extravasations[1-3]

Mechanisms and treatment regimens for non-cytotoxic drug extravasations^[1-3]