What recommendations exist for managing extravasation of angiotensin II?

What recommendations exist for managing extravasation of angiotensin II (Giapreza)?

Comment by InpharmD Researcher

Available literature addressing extravasation of angiotensin II (Giapreza) is limited and largely extrapolated from class-based vasopressor management recommendations. Vasopressor extravasation is described as a vasoconstriction-mediated injury, with consistent recommendations for immediate infusion discontinuation, attempted aspiration of residual drug, catheter removal, limb elevation, and application of warm compresses. Pharmacologic management identifies subcutaneous phentolamine as first-line therapy, typically doses at 5 to 10 mg diluted in 10 mL of 0.9% sodium chloride, injected subcutaneously in divided aliquots circumferentially around the affected area, with repeat dosing permitted every 30 to 60 minutes if needed based on clinical response. When phentolamine is unavailable or ineffective, terbutaline or topical nitroglycerin are suggested alternatives, though no angiotensin II-specific extravasation outcome data are reported.

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Background

The 2023 focused update on management of noncytotoxic extravasation injuries provides an updated synthesis of treatment strategies for extravasation events, with particular emphasis on vasopressors and hypertonic saline, including peripheral administration considerations. Within this review, angiotensin II is discussed as part of the vasopressor class, and the authors explicitly state that data for the treatment of angiotensin II extravasations are limited. The review cites a single historical report published in 1963 describing angiotensin II–associated vascular effects, in which phentolamine was used successfully, although detailed extravasation management data are not available due to the age and limited accessibility of the report. Additionally, few angiotensin II extravasations have been described following peripheral, subcutaneous, or intradermal administration, with no cases resulting in local ischemic injury or necrosis; management therefore relies on class-level vasopressor recommendations, with pharmacologic and nonpharmacologic approaches summarized in Tables 1-2. [1], [2]

A 2020 narrative review provides evidence- and consensus-based recommendations for the management of extravasation involving noncytotoxic vesicants, including vasopressors such as angiotensin II. Vasopressor extravasations are described as vasoconstriction-mediated tissue injuries and are considered medical emergencies due to a short necrosis interval that may be as brief as 4–6 hours. The review recommends prompt initiation of warm compresses to increase local circulation and administration of a vasodilator antidote to counteract vasoconstriction. Phentolamine is identified as the first-line antidote, with a typical recommended dose of 5 to 10 mg diluted in 10 to 20 mL of normal saline, administered intradermally in five divided injections circumferentially around the area of blanching, and repeat dosing every 30 to 60 minutes as needed until clinical improvement or dose-limiting hypotension occurs. Terbutaline or topical nitroglycerin are described as second-line options when phentolamine is unavailable or ineffective. The authors emphasize that timely recognition and treatment are critical to prevent ischemia, necrosis, and permanent tissue injury. [3]

A 2025 open-access evidence summary synthesized high-quality guidelines, clinical decisions, expert consensus statements, and systematic reviews addressing the safe peripheral administration of vasopressors, including recommendations for the management of extravasation events. Within the complication-management domain, the article reports that in cases of vasopressor extravasation, recommended actions include immediate cessation of the infusion, aspiration of any residual drug, removal of the peripheral catheter, and clear marking of the affected area to facilitate monitoring. The evidence further recommends subcutaneous phentolamine administration and limb elevation as first-line measures to reverse local vasoconstriction, with terbutaline or topical nitroglycerin identified as suggested alternatives when phentolamine is unavailable. These measures are presented as first-class, strongly recommended evidence within the summarized framework for managing complications associated with peripheral vasopressor infusion, without differentiation by individual vasopressor agents. [4]

The institutional extravasation management protocol from Makati Medical Center (Philippines) lists angiotensin II under vasopressors and provides operational guidance for extravasation management, recommending subcutaneous phentolamine (5-10 mg diluted in 10 mL of normal saline) administered into and around the affected area, with the option to inject through the infiltrated catheter if still in place and to repeat after 60 minutes if needed, along with dry warm compresses as supportive care. This document represents institution-specific protocol guidance and does not provide primary clinical evidence or angiotensin II-specific outcome data, but aligns with class-based vasopressor extravasation management approaches. [5]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What recommendations exist for managing extravasation of angiotensin II (Giapreza)?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Table 1. Agent-specific mechanisms of injury and suggested treatment options
Extravasation classes/agents	Mechanism of toxicity	Pharmacological treatment^a	Nonpharmacological treatment^a
Vasopressors Norepinephrine Epinephrine Dopamine Vasopressin Phenylephrine Methylene blue39 Angiotensin II Terlipressin	Vasoconstriction of veins and capillaries results in local ischemia and altered tissue metabolism	Peripheral IV extravasation: Phentolamine 5–10 mg in 10 mL of 0.9% sodium chloride injected SQ around the site of extravasation within 12 h or 1 mg diluted terbutaline (1 mg/10 mL) SQ injection into affected area 2% nitroglycerin ointment to cover affected area (may reapply every 8 h as needed) Digital epinephrine injection: Phentolamine 0.5–4.5 mg in 5 mL of 0.9% sodium chloride injected SQ around the site of extravasation or 0.5 mg concentrated terbutaline SQ injection into affected area (may repeat 15 min later) Apply 1-inch strip or 4 mm/kg for neonates of 2% nitroglycerin ointment to cover affected area (may reapply every 8 h as needed) Avoid hyaluronidase monotherapy, papaverine, conivaptan, procaine, and injectable nitroglycerin	Warm compress (avoid cold) and elevation Early surgical consult if compartment syndrome is suspected May consider liposuction for largevolume extravasations in the operating room setting
^aRefer to Table 2 for administration instructions of pharmacologic and nonpharmacologic treatments.

References:
[1] Adapted from: Stefanos SS, Kiser TH, MacLaren R, Mueller SW, Reynolds PM. Management of noncytotoxic extravasation injuries: A focused update on medications, treatment strategies, and peripheral administration of vasopressors and hypertonic saline. Pharmacotherapy. 2023;43(4):321-337. doi:10.1002/phar.2794

Table 2. Nonpharmacologic and pharmacologic treatment instructions for extravasations
Nonpharmacologic^a
Stop the infusion	Stop the intravenous push or infusion immediately the patient admits to a burning sensation, complains of pain, or if swelling, erythema, or skin discoloration is noticeable at the infusion site
Drug aspiration	The catheter or needle should be left in place to attempt aspiration of fluid from the extravasated area (particularly for grades 3 and 4 extravasations). Aspiration of the drug and surrounding fluid should be attempted with 3–5 mL of blood. If available, injection of antidotes through the infiltrated catheter allows delivery to the same injured tissue plane
Remove the needle	Remove the needle after attempted aspiration of extravasated fluid
Limb elevation	Elevate the affected limb to minimize swelling and to encourage lymphatic resorption of the drug for at least 24–48 h
Cold compress	Apply a cold compress as indicated. Cold compression may reduce subsequent inflammation and necrosis caused by most agents except for vinca alkaloids and vasopressors because cold worsens ulceration caused by these drugs. Apply for 20 min, 3 or 4 times/day for the first 48–72 h after extravasation
Warm compress	Apply a warm compress as indicated. Warm compresses are sometimes preferred for specific drug extravasation (e.g., vinca alkaloids, phenytoin, vasopressors, contrast media) to modify viscosity, increase local blood flow, and enhance drug removal
Debridement and excision	Debridement and excision of necrotic tissue should be considered if pain continues for 1–2 weeks. Surgical flushing with normal saline is often used for severe hyperosmolar extravasations. Surgical assessments may be considered sooner for decompression of compartment syndrome or liposuction in certain cases

Pharmacologic^b
	Neonatal	Pediatric	Adult
Hyaluronidase	See adult recommendations	See adult recommendations	Dilution: Withdraw 0.1 mL of hyaluronidase 150 unit/mL and place in 0.9% sodium chloride for final concentration of 15 units/mL Administer: Divide into five tuberculin syringes of 0.2 mL each and inject intradermally at five points around periphery of extravasation site May repeat in 30–60 min if no resolution
Phentolamine^c	Weight <1 kg: Use 0.1 mg/mL concentration. Inject SQ total dose of 0.05 mg divided into five tuberculin syringes of 0.1 mL each at five points on edge of swelling/blanching Weight >1–2.5 kg: Use 0.1 mg/mL concentration. Inject SQ total dose 0.1 mg divided into five tuberculin syringes of 0.2 mL each at five points on edge of swelling/blanching Weight 2.5–5 kg: Use 0.5 mg/mL concentration. Inject SQ total dose 0.25 mg divided into five tuberculin syringes of 0.1 mL each at five points on edge of swelling/blanching May repeat in 60 min	Weight ≤5 kg: see neonatal recommendations Weight >5 kg: Use 0.5 mg/mL concentration. Inject SQ total dose 0.5 mg divided into five tuberculin syringes of 0.2 mL each at five points on edge of swelling/blanching. May repeat in 60 min	Dilution: Use 5–10 mg diluted in 10 mL of 0.9% sodium chloride Administer initial dose into interstitial catheter prior to removal if available Inject another total SQ dose of 5–10 mg divided into five injections of 2 mL each on edge of swelling/blanching Digital injection: dilute 0.5–4.5 mg in 5 mL of 0.9% sodium chloride and inject SQ along edge of finger May repeat in 60 min
Terbutaline^c	Half-life too long in neonates – avoid	Do not use in patients <2 years Age ≥2 years: Dilute 1 mg in 10 mL of 0.9% sodium chloride (0.1 mg/mL). Inject dose of 0.1–0.2 mg SQ at the leading edge of the extravasated site May repeat dose after 15 min	Large extravasations: Dilute 1 mg in 10 mL of 0.9% sodium chloride (0.1 mg/mL). Inject dose of 1 mg SQ at the leading edge of the extravasated site Small extravasations (including digital): Dilute 1 mg in 1 mL of 0.9% sodium chloride (1 mg/mL) and inject 0.5 mg SQ at the leading edge of the extravasated site May repeat dose after 15 min
Topical Nitroglycerin 2% ointment	Weight ≤5 kg: dose 4 mm/kg (max 1 inch) Apply once and monitor BP every 5 × 15 min. Do not use on broken skin. May repeat every 8 h if no resolution	Weight >5 kg: Apply 1 inch to affected area Apply once and monitor BP every 5 × 15 min. Do not use on broken skin. May repeat every 8 h if no resolution	Apply 1 inch to the affected area Apply once and monitor BP every 5 × 15 min Do not use on broken skin May repeat every 8 h if no resolution
^aNonpharmacologic interventions should be applied in the order listed. ^bThis is not a comprehensive list of all pharmacological antidotes, but represents agents commonly used with complex administration techniques. ^cPhentolamine and terbutaline can be administered subcutaneously in similar manners: start with the area closest to the extravasation site and move outward using a circular or star pattern.