Extravasation of Noncytotoxic Agents: Skin Injury and Risk Classification

Abstract

Extravasations are common manifestations of iatrogenic injuries associated with intravenous therapy. Cytotoxic agents are already subject to a relatively well-defined management strategy in healthcare institutions and classified into three groups according to the extent of damage from extravasation: vesicants, irritants, and non-tissue-damaging agents. Therefore, careful monitoring and initial treatment according to the severity of the skin injury decreases the incidence of extravasation injury. In contrast, high osmolarity, acidic or alkaline, and/or vasoconstrictive activity have all been suggested as possible causes of tissue injury due to the extravasation of noncytotoxic agents. However, the severity of the injuries has not been classified. Therefore, due to a lack of awareness, case reports of severe extravasation injury caused by noncytotoxic agents are increasing. In this paper, we review case reports and animal experiments and classify the severity of extravasation injury by noncytotoxic agents into three categories. Parallel to cytotoxic agents, the classification provides appropriate warning of possible injury severity, helping medical personnel better understand the severity of tissue damage and prevent injury severity during extravasation.

1. INTRODUCTION

Extravasation is an unintentional leakage of fluid into the perivascular or subcutaneous space. Symptoms such as redness, swelling, pain, burning, erosion, blistering, ulceration, and necrosis may occur in surrounding soft tissues after leakage. These are common manifestations of iatrogenic injury that can contribute substantially to patient morbidity and length of hospital stay and cause serious liability for medical personnel with lawsuits for mismanaged cases. Therefore, cytotoxic agents are classified into three groups based on the extent of damage reported in case reports and animal experiments: vesicants, irritants, and non-tissue-damaging agents.^1–3) As guidelines for extravasation of cytotoxic agents have been issued,^4,5) preferential use of the central venous route to prevent extravasation, consideration for the fragility of the vessel and the site of puncture, and careful monitoring by specialized nurses according to the severity and initial treatment have been widely implemented, resulting in a decrease in the frequency of extravasation of cytotoxic agents.³⁾

In contrast, noncytotoxic agents are routinely used in various hospitals. Extravasation of these agents occurs quite frequently, but medical personnel is not well aware of the risks. Because most injections of noncytotoxic agents involve nontoxic ingredients, medical personnel may underestimate the potentially serious consequences of extravasation. In recent years, serious extravasation injuries have been reported more frequently with noncytotoxic agents than cytotoxic agents.⁶⁾ In this paper, we review case reports and animal experiments on the extravasation of noncytotoxic agents and classified the agents like cytotoxic agents.^1,7,8) The information is intended to provide appropriate warning to medical personnel administering noncytotoxic agents. In addition, a general initial treatment for extravasation injury is provided.

2. CLASSIFICATION OF NONCYTOTOXIC AGENTS

Generally, skin damage occurs during the extravasation of vasoconstrictors and hyperosmotic, acidic, alkaline, and absorption of refractory drugs. We classified infusions and injections approved in Japan into three categories based on the risk of skin injury: vesicants, irritants, and non-tissue-damaging agents (Tables 1, 2). Vesicants are agents that cause tissue necrosis, ulcers, and blistering, even at small extravasation volumes, because of their inherent toxicity to cells. Irritants cause an inflammatory reaction (but not necrosis) at the extravasation site. Non-tissue-damaging agents are not toxic to tissues. Clinical case reports, although non-quantitative, help establish the vesicant potential of these agents. A positive correlation between drug-induced skin ulceration in animal models and the known vesicant activity of the agents in patients has been demonstrated for several drugs.⁹⁾ Therefore, in accordance with previous studies,¹⁾ classification was based on case reports. For agents without case reports, the results of animal experiments are provided as supplementary information.

Table 1. Characteristics of Noncytotoxic Agents in Cases of Extravasation

a
	Agents	Concentration or typical dose*	Osmotic pressure ratio** (to saline) (OPR)	pH	Description of the package insert regarding extravasation
Vasoconstrictor	Adrenaline	1 mg/mL	1	2.3–5.0	Ischemic necrosis during large volume leakage
	Noradrenaline	0.05–0.3 µg/kg/min	1	2.3–5.0	Ischemic necrosis during large volume leakage
	Dopamine hydrochloride	1–5 µg/kg/min	1.0–1.4 (syringe)	3.0–5.0	Induration and necrosis during leakage
		max. 20 µg/kg/min
	Dobutamine hydrochloride	1–5 µg/kg/min	1–1.2 (syringe)	3.0–4.0	Redness, swelling, and necrosis during leakage
		max. 40 µg/kg/min
	Phenylephrine hydrochloride	1 mg/mL	1	3.5–6.0	Ischemic necrosis during large volume leakage
Hyperosmolar	Glucose	5%	1	3.5–6.5	Not stated
		10–20%	2–4
		25–50%	5–12
	Mannitol	5%	1.5	4.5–7.0	Not stated
		10–20%	3–5
	BFLUID®	—	3	6.7	Redness, infiltration, swelling, skin necrosis, and ulceration during leakage
	Iopamidol	300 mg/mL (iodine)	2.2–3.0	6.5–7.7	Redness, swelling, blistering, and vascular pain during leakage
Concentrated electrolyte	Calcium chloride (Ca2+)	2%; 0.36 mEq/mL	2	4.5–7.5	Inflammation and necrosis during leakage
	Calcium gluconate (Ca2+) (CALCICOL®)	8.5%; 0.39 mEq/mL	0.9	6.0–8.2	Not stated
	Sodium bicarbonate (Ca2+)	8.4%; 1 mEq/mL	6	7.0–8.5	Inflammation and necrosis during leakage
	Potassium chloride (K+)	0.3%; 0.04 mEq/mL	7	5.0–6.5	Not stated
	Sodium chloride (Na+)	0.9%; 0.15 mEq/mL	0.9%; 1	0.9%; 4.5–8.0	Not stated
		10%; 1.71 mEq/mL	10%; 10.6–11.6	10%; 5.0–7.0
	Magnesium sulfate (Mg2+)	12.3%; 1 mEq/mL	2	5.5–7.0	Not stated
	Magnesium sulfate hydrate·glucose (Mg2+) (MAGSENT®)	10%; 0.81 mEq/mL	4	3.5–6.0	Not stated
	Saccharated ferric oxide (Fe2+) (FESIN®)	2%; 20 mg/mL	5	9.0–10	Pigmentation, pain, dysesthesia, and swelling during leakage. In such cases, warm compress and massage to accelerate absorption. (If acute inflammatory symptoms such as pain and swelling are strong, suppress acute symptoms first with a cold compress.)
Direct Cellular Toxicity	Gabexate mesilate	2 mg/mL	1–1.3	4.0–5.5	Ulcers and necrosis during leakage
	Diazepam***	5 mg/mL	27–30	6.0–7.0	Not stated
	Digoxin***	0.25 mg/mL	-	5.5–7.5	Not stated
	Trimethoprim (TMP)·Sulfamethoxazole (SMX)***	TMP 16 mg/mL	30	9.1–9.9	Not stated
		SMX 80 mg/mL
	Hemin***	25 mg/mL	2.5–3.8	8.5–9.5	Not stated
Basic	Phenytoin***	50 mg/mL	29	12	Local discoloration, pain, edema, and necrosis during leakage
	Thiopental sodium	25 mg/mL	0.8	10.2–11.2	In case of extravasation, infiltration with a local anesthetic such as procaine, treatment with a hot compress, etc.
	Potassium canrenoate	10 mg/mL	1.2	9.0–10.0	Stated be careful not to leak, but symptoms not stated
	Furosemide	10 mg/mL	0.7–1.1	8.5–10.0	Not stated
	Omeprazole sodium	1 mg/mL	1	8.4–11.0	Not stated
	Lansoprazole	1.5 mg/mL	1	10.6–11.3	Not stated
	Aminophylline hydrate	25 mg/mL	0.1–0.7	8.0–10.0	Not stated
	Acyclovir	2.5 mg/mL	0.6–1.2	9.9–11.7	Angialgia or fragility of capillary may occur, so be careful not to leak
	Ampicillin sodium (ABPC)·Cloxacillin sodium hydrate (MCIPC)	ABPC 50 mg/mL MCIPC 50 mg/mL	1–2	7.0–10.0	Not stated
	Dantrolene sodium hydrate	0.33 mg/mL	1	9.0–10.5	Necrosis, swelling, and redness during leakage
Acidic	Nafamostat mesilate	0.02 mg/mL	0.5–1.4	3.5–4.0	Inflammation and necrosis during leakage
	Vancomycin hydrochloride	10 mg/mL	5 mg/mL; 1	5–50 mg/mL; 2.5–4.5	Necrosis during leakage
	Nicardipine hydrochloride	1 mg/mL	1	3.0–4.5	Inflammation and induration during leakage
	Hydroxyzine hydrochloride	25 mg/mL	0.8	3.0–5.0	Phlebitis and transient hemolysis during leakage
Mechanical compression	Propofol	10 mg/mL	0.9–1.2	6.0–8.5	Local pain, swelling, hematoma, and tissue necrosis during leakage
	Soybean oil (INTRALIPOS®)	20%	1	6.5–8.5	Redness, infiltration, swelling, skin necrosis, and ulceration during leakage

This table is not a comprehensive list of all agents that can cause injury and reflects the most commonly reported agents that have been well-described. * General-purpose concentration in Japan or concentration refer to the package insert. ** Approximately. *** Excipient: propylene glycol.

b
	Agents	Concentration or typical dose*	Risk**	References	Proposed mechanisms of tissue injury	Recommended administration route
Vasoconstrictor	Adrenaline	1 mg/mL	V	12, 13	ad	In cases of high risk of leakage, administered via the central vein, whenever possible
	Noradrenaline	0.05–0.3 µg/kg/min	V	14	ad	In cases of high risk of leakage, administered via the central vein, whenever possible
	Dopamine hydrochloride	1–5 µg/kg/min	(20 mg/mL; I)**	25	ad	Especially high doses (>5 µg/kg/min) should be administered via the central vein, whenever possible
		max. 20 µg/kg/min	>5 µg/kg/min; V	16
	Dobutamine hydrochloride	1–5 µg/kg/min	(3 mg/mL; I)**	21	ad	Especially high doses (≥ 10 µg/kg/min) should be administered via the central vein, whenever possible
		max. 40 µg/kg/min	≥ 10 µg/kg/min; V	11,15
	Phenylephrine hydrochloride	1 mg/mL	(N)**	21	ad	In cases of high risk of leakage, administered via the central vein, whenever possible
Hyperosmolar	Glucose	5%	(N) **	21	-	Especially osmotic pressure ratio of 3 or higher should be administered via the central vein, whenever possible
		10–20%	I	15	b
		25–50%	V	30, 31
	Mannitol	5%	(N)**	21	-
		10–20%	I	15	b
	BFLUID®	-	(I)**	21	b
	Iopamidol	300 mg/mL (iodine)	≤OPR 2.8; I	11	bc
			≥OPR 3.7; V	32
Concentrated electrolyte	Calcium chloride (Ca2+)	2%; 0.36 mEq/mL	≥1.5%; V	15, 41	bc	In cases of high risk of leakage, administered via the central vein, whenever possible
	Calcium gluconate (Ca2+) (CALCICOL®)	8.5%; 0.39 mEq/mL	8.5%; V	15	bc	In cases of high risk of leakage, administered via the central vein, whenever possible
	Sodium bicarbonate (Ca2+)	8.4%; 1 mEq/mL	≥4.2%; V	15, 45	b	In cases of high risk of leakage, administered via the central vein, whenever possible
	Potassium chloride (K+)	0.3%; 0.04 mEq/mL	(0.3%; 0.04 mEq/mL; N)**	45	b	Especially 0.04 mEq/mL or higher should be administered via the central vein, whenever possible
			≥0.75%; 0.1 mEq/mL; V	15, 37, 43
	Sodium chloride (Na+)	0.9%; 0.15 mEq/mL 10% ;1.71 mEq/mL	(0.9%; N)**	45	b	Especially osmotic pressure ratio of 3 or higher should be administered via the central vein, whenever possible
			(3%; I) **	45
			10%; V	44
	Magnesium sulfate (Mg2+)	12.3%; 1 mEq/mL	(0.6%; 0.05 mEq/mL; N)**	45	b	Less than 0.05 mEq/mL is desirable when administered via the peripheral route
			(12.3%; 1 mEq/mL; V)**	45
			15%; V	44
	Magnesium sulfate hydrate·glucose (Mg2+) (MAGSENT®)	10%; 0.81 mEq/mL	(10%; V)**	45	b	In cases of high risk of leakage, administered via the central vein, whenever possible
	Saccharated ferric oxide (Fe2+) (FESIN®)	2%; 20 mg/mL	(V)**	45	bc	In cases of high risk of leakage, administered via the central vein, whenever possible
Direct Cellular Toxicity	Gabexate mesilate	2 mg/mL	V	47	cd	Less than 2 mg/mL is desirable when administered via the peripheral route. However, necrosis occurs even at concentrations below 2 mg/mL
	Diazepam***	5 mg/mL	V	44	bc	By diluting the agent approximately 14-fold, both osmotic effects and necrosis caused by propylene glycol can be avoided.
	Digoxin***	0.25 mg/mL	V	44	cd	Propylene glycol-induced necrosis can be avoided by diluting the agent approximately 14-fold
	Trimethoprim (TMP)· Sulfamethoxazole (SMX)***	TMP 16 mg/mL SMX 80 mg/mL	NA	-	c	Propylene glycol-induced necrosis can be avoided by diluting the agent approximately 14-fold
	Hemin***	25 mg/mL	NA	-	c	Propylene glycol-induced necrosis can be avoided by diluting the agent approximately 15-fold
Basic	Phenytoin***	50 mg/mL	V	52	bcd	Use of phenytoin's prodrug fosphenytoin is reasonable because the product remains soluble without propylene glycol and is less alkaline (pH 8.5–9.1, osmotic pressure ratio 1.9)
	Thiopental sodium	25 mg/mL	V	15	d	In cases of high risk of leakage, administered via the central vein, whenever possible
	Potassium canrenoate	10 mg/mL	(V) **	21	d	In cases of high risk of leakage, administered via the central vein, whenever possible
	Furosemide	10 mg/mL	V	53	d	In cases of high risk of leakage, administered via the central vein, whenever possible
	Omeprazole sodium	1 mg/mL	I	****	d	Careful administration via the peripheral route
	Lansoprazole	1.5 mg/mL	(V) **	21	d	In cases of high risk of leakage, administered via the central vein, whenever possible
	Aminophylline hydrate	25 mg/mL	V	51	d	In cases of high risk of leakage, administered via the central vein, whenever possible
	Acyclovir	2.5 mg/mL	I	54	d	Careful administration via the peripheral route
	Ampicillin sodium (ABPC)· Cloxacillin sodium hydrate (MCIPC)	ABPC 50 mg/mL MCIPC 50 mg/mL	(I)**	21	d	Careful administration via the peripheral route
	Dantrolene sodium hydrate	0.33 mg/mL	I	****	d	Careful administration via the peripheral route
Acidic	Nafamostat mesilate	0.02 mg/mL	(0.02 mg/mL; N)**	21	d	Less than 0.02 mg/mL is desirable when administered via the peripheral route, as described in the package insert
			(10 mg/mL; V)**	21
	Vancomycin hydrochloride	10 mg/mL	(4.5 mg/mL; N)**	21	d	Less than 10 mg/mL is desirable when administered via the peripheral route
			<10 mg/mL; I	44
			>10 mg/mL; V	44
	Nicardipine hydrochloride	1 mg/mL	V	44	d	In cases of high risk of leakage, administered via the central vein, whenever possible
	Hydroxyzine hydrochloride	25 mg/mL	V	55	d	In cases of high risk of leakage, administered via the central vein, whenever possible
Mechanical compression	Propofol	10 mg/mL	V	59, 60	e	In cases of high risk of leakage, administered via the central vein, whenever possible. Rare reports of tissue necrosis may be related to the large extravasated volume due to infusion pressure.
	Soybean oil (INTRALIPOS®)	20%	V	15	e	In cases of high risk of leakage, administered via the central vein, whenever possible

Risk derived from available report, subject to review and change as further evidence become available. abbreviations: V, vesicant; I, irritant; N, non-tissue damaging; NA, not available; OPR, osmotic pressure ratio** (to saline). a; ischemic necrosis due to vasoconstrictor b; osmotic damage c; direct cellular toxicity d; pH e; mechanical compression (all drugs can cause injury by this mechanism if large volumes of the solution are extravasated). * General-purpose concentration in Japan or concentration refer to the package insert. ** Those with only animal data are shown in parentheses. *** Excipient:propylene glycol. **** Unpublished report collected by pharmaceutical companies.

Table 2. Three Classifications of Injury during Extravasation of Noncytotoxic Agents

	Vesicants	Irritants	Non-tissue damaging
Vasoconstrictor	Adrenaline 1 mg/mL　 Noradrenaline 0.05–0.3 µg/kg/min　 Dopamine hydrochloride >5 µg /kg/min　 Dobutamine hydrochloride ≥10 µg/kg/min	(Dopamine hydrochloride 20 mg/mL)* (Dobutamine hydrochloride 3 mg/mL)*	(Phenylephrine hydrochloride 1 mg/mL)*
Hyperosmolar	25–50% Glucose　 ≥OPR**3.7 Iopamidol	10–20% Glucose　 10–20% Mannitol 　(BFLUID®)*　 ≤OPR**2.8 Iopamidol	(5% Glucose)*　 (5% Mannitol)*
Concentrated electrolyte	≥1.5% Calcium chloride　 8.5% CALCICOL®　 ≥4.2% Sodium bicarbonate　 ≥0.75% Potassium chloride　 10% Sodium chloride　 15% Magnesium sulfate　 (12.3% Magnesium sulfate)*　(MAGSENT®)* (FESIN®)*	(3% Sodium chloride)*	(0.3% Potassium chloride)*　 (0.9% Sodium chloride)*　 (0.6% Magnesium sulfate)*
Direct cellular toxicity	Gabexate mesilate 2 mg/mL 　 Diazepam 5 mg/mL　 Digoxin 0.25 mg/mL
Basic	Phenytoin 50 mg/mL　 Thiopental sodium 25 mg/mL　 (Potassium canrenoate 10 mg/mL)*　 Furosemide 10 mg/mL　 (Lansoprazole 1.5 mg/mL)*　 Aminophylline hydrate 25 mg/mL	Omeprazole sodium 1 mg/mL***　 Acyclovir 2.5 mg/mL　 (Ampicillin sodium 50 mg/mL　 ·cloxacillin sodium hydrate)*　 Dantrolene sodium hydrate 0.33 mg/mL***
Acidic	(Nafamostat mesilate 10 mg/mL)*　 Vancomycin hydrochloride >10 mg/mL　 Nicardipine hydrochloride 1 mg/mL　 Hydroxyzine hydrochloride 25 mg/mL	Vancomycin hydrochloride <10 mg/mL	(Nafamostat mesilate 0.02 mg/mL)*　 (Vancomycin hydrochloride 4.5 mg/mL)*
Mechanical compression	Propofol 10 mg/mL　 INTRALIPOS®

This table is not a comprehensive list of all agents that can cause injury and reflects the most commonly reported agents that have been well-described. * Only animal data are shown in parentheses. ** Approximate osmotic pressure ratio (to saline). *** Unpublished report collected by pharmaceutical companies.

The agents were selected because extravasation was mentioned in their package inserts, or necrosis was induced at the extravasation region, although extravasation was not mentioned in the package insert. However, we do not provide a comprehensive list of all agents that can cause injury and focus on the most commonly reported extravasating agents. In addition, glucose and D-mannitol were included as hyperosmotic agents, and lansoprazole and omeprazole sodium were included as alkaline agents.

3. MECHANISM OF TISSUE INJURY

Extravasation injury can occur via five mechanisms: (1) ischemic necrosis due to vasoconstrictors, (2) osmotic pressure gradient across the cell membrane, (3) direct cellular toxicity, (4) pH and buffering capacity, and (5) mechanical compression.¹⁰⁾ Injuries during the leakage of cytotoxic agents are mainly related to direct cellular toxicity. For noncytotoxic agents, the contribution of other pathophysiological mechanisms is significant. Osmotically active substances include hypertonic solutions containing cations, such as ionized calcium and potassium. Hypertonic solutions cause osmotic imbalance across the cell membrane, inhibiting cell membrane function and causing skin injury.

3.1. Vasoconstrictors

Extravasated vasopressors cause skin injury due to local ischemia induced by vasoconstriction of veins, capillaries, and vasa vesorum.¹¹⁾ The clinical course is severe, with erythema, swelling, pain, blistering, and necrosis. Furthermore, catecholamines used in cardiac arrest, except adrenaline, are injected forcefully using an automated syringe pump, and the leak can easily increase. In addition, patients are often unable to complain of pain due to unconsciousness, even if a leak occurs. In particular, leaked adrenaline or noradrenaline can lead to severe necrosis requiring grafting and extremity amputation.^12–14)

Numerous case reports of dopamine and dobutamine-induced ischemia and extravasation have occurred when high doses (>5, ≥10 µg/kg/min, respectively) were infused.^11,15,16)

In contrast, low-dose dopamine and dobutamine (<3 µg/kg/min) affect dopaminergic receptors selectively, with no considerable α-stimulation,^11,15,16) generally resulting in only inflammation and edema in the event of leakage. Cases of necrosis are rare and can cause severe vasoconstriction when high concentrations are achieved in the tissue secondary to the extravasation of low-dose dopamine and dobutamine.^16,17) Nevertheless, necrosis reports are often causally unknown because of the route of administration of multiple agents.^18,19) There is only one reported extravasation-induced injury with a phenylephrine and corticosteroid and antibiotic solution,²⁰⁾ and no reports of leakage injury with phenylephrine alone exist. No injury was observed when 1 mg/mL phenylephrine was leaked in animal experiments.²¹⁾ Although phenylephrine has a vasoconstrictive effect, this effect is weaker than that of epinephrine²²⁾; thus, the risk of skin injury is low.

In nearly all cases of necrosis caused by leakage, phenylephrine was administered via the peripheral route. Although these vasoconstrictors are sometimes unavoidably administered through a peripheral vein in emergencies, as recommended by the American Heart Association guidelines, administration using a central vein to prevent leakage is advisable when administering regularly.²³⁾ Multiple factors contribute to extravasation injury. The extent of damage from vasoconstrictor function itself remains unclear.¹¹⁾

The extent of damage is associated with the degree of vasoconstriction activity of the agent in animal experiments, in the order of noradrenaline = adrenaline > dopamine = dobutamine.^21,24,25) The extravasation of acidic solutions, such as adrenaline (pH 2.3–5.0), noradrenaline (pH 2.3–5.0), dopamine (pH 3.0–5.0), and dobutamine (pH 3.0–4.0), induces skin lesions. One of the causes of injury is presumably non-physiological pH. However, diluted hydrochloric acid or acetic acid solutions at pH 3.0–5.0 without catecholamine did not induce necrosis or ulcers in animal experiments, suggesting catecholamines themselves cause skin injury. Thus, the severity of injury induced by extravasated catecholamines may be defined by the strength of the vasoconstriction activity and the subsidiary effect of the low pH.

Phentolamine, an α-receptor antagonist, is the only antidote approved by the U.S. Food and Drug Administration (FDA) for catecholamine extravasation. Phentolamine (5 mg dissolved in 10 mL of 0.9% sodium chloride) antagonizes vasoconstriction and prevents necrosis. However, it is off-label in Japan, and its use should not exceed 0.1–0.2 mg/kg or 5 mg total dose. It is most effective if the treatment is started early (within 12 h).^23,26) In addition, all agents mentioned below are off-label for extravasation injuries in Japan but commonly used overseas. Terbutaline, a β2-stimulating smooth muscle relaxant, reduces leak injury and is recommended for subcutaneous administration when phentolamine is unavailable.¹⁹⁾ Hyaluronidase, an enzyme that facilitates the degradation of the extracellular matrix, is not used because it may further expand vasoconstriction.¹¹⁾ Nitroprusside is also ineffective despite its potent vasodilator action. Nitroglycerin 2% ointment application eliminates ischemia during dopamine leakage and may be effective, but it should be used with caution.²⁷⁾ Nitroglycerin 2% ointment is not approved in Japan.

3.2. Hyperosmotic Preparations

High osmotic stress directly leads to proteins and DNA damage, the formation of reactive oxygen species, and the induction of apoptosis.¹¹⁾ When hyperosmotic agents are administered through the peripheral vein, phlebitis is induced. The guidelines recommend that the osmotic ratio of the infusions to saline be adjusted to less than 3 to prevent phlebitis induced by the administration of infusion agents via a peripheral vein.²⁸⁾ Extravasated hyperosmolar agents cause a shift in fluid from the intracellular to the extracellular space, resulting in the dysfunction of cellular membranes and dysregulation of cell volume. Because these effects continue until the high osmolarity of the extravasated solution reaches isotonic osmolarity, extravasated hyperosmolar agents can cause severe skin injuries, even in small quantities.^29,30) However, it is not clear at what osmotic pressure level extravasation can cause skin injury. In animal experiments, the osmotic solutions, glucose and D-mannitol solutions, caused approximately the same severity of injury at the same concentration, and extravasation induced severe skin damage, such as ulceration, in an osmolarity-dependent manner. Specifically, an osmotic pressure ratio of 2 or higher induces inflammatory cell infiltration into the dermis and skin muscles. An osmotic pressure ratio of 5 or higher induces collagen degeneration and necrosis in the epidermal, dermal, and subcutaneous tissues. In summary, an osmotic pressure ratio of 2–4 can be classified as an “irritant,” whereas 5 or higher can be classified as a “vesicant”²⁵⁾ (Table 2). Several skin injury cases due to 10% or higher (osmotic pressure ratio of 2 or higher) glucose-induced extravasation have been reported, especially considerable necrosis due to glucose leaks of 50% or higher (osmotic pressure ratio of 10 or higher).^30,31) Extravasation of parenteral nutrition is frequently reported because it is generally administered in larger doses, with a corresponding increase in the amount of leakage. In addition, the guidelines recommend that agents with an osmotic pressure ratio of 3 or higher should not be administered peripherally,²⁸⁾ and 50% glucose may be administered intravenously via a peripheral vein to treat severe hypoglycemia with consciousness disturbance. Thus, medical personnel should carefully monitor the development of extravasation injuries during high-concentration glucose infusions. The development of extravascular injury caused by contrast media is due to multiple factors, including the cytotoxicity of the contrast media or osmotic pressure, with case reports of necrosis even when the osmotic pressure ratio was lower than 5.³²⁾ Hyaluronidase is commonly used overseas for the treatment of hyperosmotic agent extravasation³³⁾ but is used off-label for extravasation injuries in Japan. It promotes agent diffusion by degrading hyaluronic acid in the connective tissue. However, if there is an infected lesion or tumor at the site of leakage, it should not be administered because of the risk of metastasis or invasion.³⁴⁾

3.2.1. Calcium Preparations

Extravasation injuries caused by calcium solutions have been reported most frequently among noncytotoxic agents.¹⁵⁾ The injury occurs due to direct protein denaturation by calcium salts, possibly caused by the reaction of phosphorus and calcium to form hydroxyapatite, leading to calcification such as calcinosis cutis and the degree of calcium-related cutaneous necrosis.^35,36) Neonates have high blood phosphorus levels and are prone to calcification when exposed to calcium preparations.^35,36) There have been many reports of severe injury due to calcium preparations extravasation.^37,38) Hence, great care should be taken, especially in neonates. Calcium solutions (0.27–1.36 mEq/mL) cause serious and prolonged injury,^39,40) regardless of the osmotic pressure ratio. It is important to recognize this potential risk of drug extravasation. Hyaluronidase is an off-label drug for extravasation injury in Japan but is commonly used to treat calcium extravasation overseas. It should be used within 60 min after a leak.⁴¹⁾ Sodium thiosulfate hydrate is also effective for treating calcium extravasation because of its ability to dissolve precipitated calcium salts⁴²⁾; however, it has been approved only for the treatment of cyanide and arsenic poisoning in Japan.

3.2.2. Potassium Preparations

Potassium chloride solution did not induce skin injury in an animal model at the maximum concentration (K⁺ 0.04 mEq/mL) described in the package insert. Therefore, no injury is expected after extravasation of the widely used ≤0.04 mEq/mL K⁺ solution. Extravasation of a ≥0.1 mEq/mL K⁺ solution is associated with a high risk of skin injury because of its osmotic imbalance across the cell membrane.^15,37,43) Therefore, extravasation should be carefully monitored when high potassium concentrations have to be administered, such as in patients requiring potassium and fluid restriction because of cardiac dysfunction.

3.2.3. Sodium Chloride Preparations

Several cases of skin necrosis due to leakage of sodium chloride injections of ≥10% have been reported.⁴⁴⁾ Necrosis caused by 10% sodium chloride (Na⁺ 1.71 mEq/mL) was also observed in animal experiments.⁴⁵⁾ Because the osmotic pressure ratio of 10% sodium chloride is approximately 11, osmotic pressure is likely involved in the injury induction. In contrast, 3% sodium chloride (Na⁺ 0.51 mEq/mL, osmotic pressure ratio: 3.7), a common concentration for peripheral administration, caused only inflammation in the lesion. Therefore, although there are few opportunities to administer agents containing electrolytes without dilution, extravasation must be given special attention when administering sodium solutions at concentrations >3%.

3.2.4. Magnesium Preparations

There have been several case reports of necrosis caused by 15% magnesium sulfate hydrate solution commercially available overseas.⁴⁴⁾ The injury caused by MgSO₄ is concentration-dependent in animal experiments.⁴⁵⁾ A diluted solution (0.6% magnesium sulfate hydrate solution; Mg²⁺ 0.05 mEq/mL) widely used for electrolyte supplementation did not induce injury; however, an undiluted solution (12.3% magnesium sulfate hydrate injection; Mg²⁺ 1 mEq/mL) induced necrosis. The magnesium sulfate hydrate glucose solution MAGSENT^® (10% MgSO₄, 10% glucose; Mg²⁺, 0.81 mEq/mL), used to treat eclampsia, caused more severe injury than 12.3% magnesium sulfate hydrate (Mg²⁺, 1 mEq/mL), despite its low Mg²⁺ concentration. This is because magnesium sulfate hydrate glucose has a very high osmotic pressure ratio of 3.5–6.0. Therefore, medical personnel must pay attention to not only the concentration of the electrolyte but also the osmotic pressure of magnesium preparations.

3.2.5. Iron Preparations

Several cases of extravasation of iron preparations have been reported.⁴⁶⁾ The animal experiments also showed that the leakage of iron oxide saccharide injection FESIN^® (2%; Fe²⁺ 20 mg/mL) induced skin ulceration accompanied by iron pigmentation.⁴⁵⁾ The package insert states that caution for pigmentation during leakage is required. Medical personnel needs to be aware of the characteristic symptoms.

3.3. Non-anticancer Cytotoxic Drug Preparations

Gabexate has been specially alerted by the Japan Council for Quality Health Care due to a series of reports of serious extravasation injuries.⁴⁷⁾ Since gabexate can damage the vascular wall, causing phlebitis, induration, ulceration, and necrosis along the vessels, the concentration for peripheral administration should be 0.2% or less.⁴⁷⁾ However, even at 0.2% concentration, necrosis can occur once it leaks. Necrosis of the skin due to gabexate leakage has also been reported in animal models.²¹⁾ Caution should be exercised when using a drug with strong cellular toxicity.

Propylene glycol, used as an additive in injectable formulations, causes contact dermatitis due to its skin irritation.⁴⁸⁾ In animal experiments, extravasation injury caused by diazepam, digoxin, and carbazochrome injections was analyzed in rats. Diazepam and digoxin contain high concentrations of propylene glycol (400 and 415 mg/mL, respectively), causing degeneration of skin collagen and ulceration.²¹⁾ Drugs that can be injected intramuscularly generally cause less damage to the skin; however, several clinical cases of necrosis have also been reported with diazepam and digoxin, which can be injected intramuscularly.⁴⁴⁾ Although there is no mention of extravasation in the package inserts of either drug, they are clinically irritating when extravasated and painful when injected intramuscularly. Irritation may be caused by the vehicle rather than by the active drug,⁴³⁾ and caution is needed.

Necrosis and other histological changes were not observed with carbazochromes containing 30 mg/mL propylene glycol. Propylene glycol (416 mg/mL) solution without drug was classified as a necrotizing agent. Hence, it is clear that propylene glycol itself causes severe skin injury. Therefore, particular attention should be given to the extravasation of agents from preparations containing high concentrations of propylene glycol, such as diazepam and digoxin injections. Other injectable drugs approved in Japan with propylene glycol content of 400 mg/mL or higher are phenytoin, trimethoprim-sulfamethoxazole, and hemin. Trimethoprim-sulfamethoxazole and hemin injections must not be strictly administered undiluted and must be diluted to a concentration below a propylene glycol concentration of 30 mg/mL before administration. As an alternative to phenytoin, the use of the phenytoin prodrug fosphenytoin is reasonable because the product without propylene glycol is less alkaline.

3.4. Acidic and Basic Preparations

Acid exposure commonly leads to cellular desiccation, coagulative necrosis, and eschar formation. Exposure of tissue to an alkaline solution leads to the formation of dissociated hydroxide ions that extensively penetrate tissues, leading to protein dissolution, collagen destruction, vasoconstriction, and apoptosis. Hydroxide ions continue to penetrate the tissue until proteins and acid substances fully neutralize them. Alkaline exposures require more attention because it has the highest propensity for severe tissue damage due to deeper tissue penetration than acid exposure.⁴⁹⁾ It has been inferred from animal experiments and case reports that there is a risk of tissue injury with alkaline and acidic injections.^44,50) Skin necrosis by thiopental (pH 10.2–11.2) extravasation in human and animal models has been reported.^15,50) Extravasation of alkaline aminophylline hydrate (pH 8–10) and phenytoin (pH 12) resulted in tissue necrosis.^15,51) As described above, fosphenytoin, a water-soluble phosphate ester prodrug of phenytoin with a pH of 8.6–9, was developed to overcome infusion complications associated with phenytoin solution into surrounding tissue, causing necrosis.⁵²⁾ However, there is no clear evidence of a correlation between pH values and the degree of extravasation injuries. Even at a similar pH, the injury severity may be different. For example, furosemide, omeprazole sodium, and dantrolene sodium hydrate have osmotic pressure ratios of 0.7–1.1, 1, and 1, respectively, and pH values of 8.5–10.0, 8.4–11.0, and 9.0–10.5, respectively.

Skin necrosis by furosemide extravasation in human and animal models has been reported.^21,53) In contrast, there are only a few unpublished reports of omeprazole and dantrolene leakage collected by pharmaceutical companies, which are limited to redness, no necrosis, and no inflammation or necrosis observed in animal experiments. Cases of acyclovir leakage injury are characteristic.⁵⁴⁾ Most agent-induced extravasation injuries commonly present with erythema and, in severe cases, necrosis. However, this is not the case with acyclovir, which mainly causes inflammation and phlebitis and, in severe cases, severe chemical inflammation but rarely ulceration. In animal experiments at clinical concentrations (2.5 mg/mL), an inflammatory reaction (but not necrosis) has been reported.²¹⁾ Notably, although they are classified as irritants, they require utmost caution regarding severe chemical inflammation. The acidic injectable solutions nicardipine hydrochloride (pH 3.0–4.5) and hydroxyzine hydrochloride (pH 3.0–5.0) reportedly cause necrosis during leakage.^44,55)

Vancomycin is necrotizing, with reports of blistering injury and debridement at ≥10 mg/mL.^56,57) However, David et al. reported that vancomycin is inflammatory at <10 mg/mL.⁴⁴⁾ Animal experiments also showed necrosis at 25 mg/mL (pH 3.4); however, no necrosis was seen at 4.5 mg/mL (pH 3.7).²¹⁾ Extravasation injury is reduced by dilution; however, because the change in pH due to dilution of the injectable preparation with water or saline is slight, the pH of the injection alone cannot explain the injury occurrence. The local pH fluctuation at the leakage point greatly depends on the buffering capacity of the injection solutions. Non-buffered solutions are less likely to cause injury. Smolders et al. also reported that buffering capacity is important in evaluating the severity of extravasation injury.⁵⁸⁾

3.5. Mechanical Compression

The chemical properties of the propofol preparation are neutral (pH 7.0–8.5) and isotonic. Animal experiments did not show induction of necrosis by the drug.⁵⁰⁾ However, several cases of necrosis and compartment syndrome due to extravasation have been reported.^59,60) Compartment syndrome is defined as an increase in pressure within a closed compartment, a muscle compartment, leading to a compromise in the microcirculation of the tissue within. If left untreated, permanent damage to the soft tissue can occur.⁶¹⁾ Even less invasive propofol can induce tissue injury if a large volume extravasates because high hydrostatic pressures lead to tissue ischemia. In addition, forced administration by a syringe pump may cause compartment syndrome due to the leakage of a large amount of drug if detected too late. Ong and Van Gerpen proposed a new mechanism of tissue injury whereby drugs with limited solubility and ability to be absorbed into the bloodstream persist in the extravasated space. Propofol, often contained in a lipid carrier solution, seems particularly prone to cause necrosis and compartment syndrome because of its limited ability to disperse in the tissues and be absorbed into the bloodstream.¹⁰⁾

4. MANAGEMENT OF EXTRAVASATION

Risk factors for extravasation can be classified into (1) patient-related (small and fragile veins in infants, children, or elderly patients, vessels that may burst easily, and cancer patients with hardened and thickened vessels due to frequent venipuncture), (2) procedure-related (untrained or inexperienced staff and inadequate choice of site of vascular access), and (3) drug-related (drug property, high concentration, volume of extravasation, and duration of exposure).⁶²⁾ Medical personnel’s awareness of these risks is the most important factor in preventing extravasation. The incidence of extravasation is 23–78% in neonates and 11–28% in children⁶³⁾ for all agents as well as 0.5–6.5% in adults for cytotoxic agents.⁴⁾ Children are particularly vulnerable to extravasation because of their small and fragile veins, capillary leakage, flexible subcutaneous tissue, inability to pay attention to infusion leaks, and inability to express abnormality, leading to serious complications.⁶⁴⁾ The puncture site is important, and administration from veins such as the dorsum of the hand and movable parts near joints should be avoided; however, if administration from these sites is unavoidable, leakage should be carefully considered.⁶²⁾ Most of the available data on extravasation are related to peripheral intravenous lines.^37,65) For central venous catheters and implanted venous access devices, extravasation is less frequent than peripheral venous routes but may delay the diagnosis of extravasation because it might easily escape attention.^65,66) The volume of extravasated products and the duration of exposure increase the risk of tissue damage, emphasizing the importance of rapid management. Application of dressing on the access and explaining to the patient to notify them of any discomfort at the vascular access site are most useful for early detection. Furthermore, the assumption that the infusion pump alarm will sound to indicate extravasation may be false. It is important to note that “infusion pumps do not always sound an alarm for extravasation.” If leakage occurs despite the utmost care, the infusion of the agent should be stopped immediately. As much of the infiltrated agent as possible should be removed from the catheter. In addition, if the injury progresses or there is a necrotic infection, the effects of the leaked agent should be removed by surgical excision.

Systematic cooling and warming methods, such as the compression time and temperature for extravasation injury, have not been determined.^3,15,44) The reported application of ice four times daily for 20 min each for 1–2 d together with compression elevation (PRICE)⁶⁷⁾ and cryotherapy are considered to be protective measures for ankle-joint sprains and muscle bruises.⁶⁸⁾ However, a comparative study in doxorubicin-injected mice reported that a single 3-h cooling session was more effective than four-times daily cooling for 20 min.⁶⁹⁾ Cooling with a cold pack (18–20 °C) for 3 h reduced inflammation and ulceration caused by thiopental and propofol. However, treatment with a hot pack (40–42 °C) for 3 h resulted in lesion enlargement in rats. The mechanism of cool compression is possibly the induction of vasoconstriction, resulting in reduced dispersion of these agents. The assumed mechanism of hot compression is that local blood vessels are dilated, and absorption of the leaked agent is accelerated. Dorr and Alberts reported that warming could reduce the extravasation injury caused by vinca alkaloids through incompletely understood mechanisms.⁸⁾ The manufacturer recommended that thiopental extravasation should be managed by infiltration with a local anesthetic, such as procaine injection, and warming. Possibly, warming alone does not have an injury-inhibiting effect against extravasation. However, local warming in combination with an acidic agent (e.g., procaine) could improve extravasation injury induced by alkaline agents because warming enhances the neutralization of alkaline agents by procaine resulting from the promotion of their dispersion.¹⁵⁾

Prompt management of tissue damage induced by extravasated agents has been proposed, including elevation of the affected body part, cooling or warming of local tissue, and surgical excision and/or pharmacologic interventions.^3,5) Unfortunately, it is difficult to properly evaluate the efficacy of these agents because the evidence for the management of extravasation is largely limited to case reports. Case series describing attempted treatment modalities do not include rigorous controls needed for an unequivocal test of efficacy.

5. CONCLUSION

Recognizing the characteristics and risk factors specific to noncytotoxic agents is important. Careful monitoring is essential to prevent the extravasation as well as cytotoxic agents. However, even for noncytotoxic drugs that induce severe skin injury, no warning of extravasation risk is often given in package inserts. The lack of accurate information is a major issue when estimating the risk of tissue injury caused by extravasation.

Recently, noncytotoxic agents have been classified into three categories: vesicants, irritants, and non-tissue-damaging agents. We discuss the importance of the leaked solution’s amount, concentration, duration, buffering capacity, and patient background in estimating the degree of skin injury. This information aims to assist medical personnel in predicting and treating skin damage caused by the extravasation of non-cytotoxic drugs and should be reevaluated regularly as new data emerge. We expect to improve patient QOL with proper precautions and appropriate initial treatment when extravascular leakage occurs.

Conflict of Interest

The authors declare no conflict of interest.

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