Phentolamine is a reversible alpha-adrenergic receptor antagonist.14 For neonates, the provider should perform a 1:10 dilution of the commercial 5 mg/mL phentolamine to a concentration of 0.5 mg/mL, followed by 5 injections of 0.2 mL of phentolamine into the area of extravasation.19 For infants, children, and adults, 5 mg of phentolamine reconstituted with 5 mL of normal saline (1 mg/mL) or a 1:5 dilution should be performed of the commercially available 5 mg/mL phentolamine to attain a final concentration of 1 mg/mL phentolamine. The solution should be injected in 0.5–1 mL aliquots 5 times around the injection site using a 25-gauge or 27-gauge needle.25 Phentolamine’s effects are time dependent with no beneficial outcome observed after 13 hours of the injury14 (Fig. 4). Nitroglycerin can be given to augment phentolamine-mediated vasodilation. Topical application of 2.5 cm of 2% nitroglycerin paste with reapplication every 8 hours has been shown to initiate reperfusion.14
Osmotically Active Agents
Infiltration of hypertonic solutions [TPN, peripheral parenteral nutrition (PPN), dextrose > 10%, sodium bicarbonate, potassium, and calcium 26) causes an imbalance in the equilibrium between the intracellular and extracellular compartments, causing fluid shifts, cellular dysfunction, and cell damage/death. Accumulation of fluid further compromises the tissue compartment through hypoperfusion and subsequent tissue necrosis14 (Fig. 5). A retrospective study on 352 patients receiving PPN found a 40% incidence of phlebitis or infiltration. Those receiving PPN with osmolarity greater than 1,000 mOsm/L had a 17% incidence versus 7% incidence in patients receiving PPN with an osmolarity less than 1,000 mOsm/L.27 In these cases, the patient must be evaluated and monitored for compartment syndrome, with a low threshold to obtain a compartment pressure or perform fasciotomies if clinically suspicious (positive if greater than 30 mm Hg).28
Hyaluronidase is often utilized for treating hypertonic extravasations, though not Food and Drug Administration (FDA) approved for this indication.14 Although there are conflicting data regarding its efficacy, most case studies report that hyaluronidase augments dispersion of the extravasated agent.29 However, no randomized clinical studies have been performed to date.30 Hyaluronidase functions via depolymerization of glycosaminoglycans such as chondroitin sulfate and hyaluronic acid, which is thought to increase tissue permeability and subsequently aid in dispersion of the infiltrated agent (technique described below under cytotoxic drugs section). Local injection of hyaluronidase and saline washout is the current principle modality to treat severe TPN-associated extravasations; however, this is based on limited studies14 (Fig. 5). Hyaluronidase was shown to be successful in the treatment of 2 cases of TPN extravasations with improvement in 6–12 hours.31
Contrast media extravasation carries an incidence of 0.1–0.9%32,33 and is usually minor and self-resolving; however, it can escalate to more serious complications.32,34 Extravasated contrast media is toxic to the surrounding tissues and is associated with an inflammatory response that peaks between 24 and 48 hours.32 The mechanism of toxicity is similar to that of osmotically active agents, as its hypertonicity results in fluid shifts.32
There is no evidence-based consensus on management; however, most commonly, the limb is elevated and treated with a warm compress.33 The efficacy of this maneuver is not proven.16,32 The attempted aspiration of contrast media, liposuction, or injection of local therapies such as hyaluronidase or corticosteroids has no evidential support for the treatment of a contrast media extravasation.32 As in all extravasation injuries, monitoring of the patient for progression of symptoms, such as progressive neurologic or vascular complications, is appropriate and necessary.33
Cytotoxic drugs are grouped into 5 categories: irritants, inflammitants, exfoliants, vesicants, and neutrals (Table 4),11 with each causing characteristic clinical pictures of soft-tissue damage. Below, we will review the described pharmacologic interventions for these chemotherapeutic extravasations.
Hyaluronidase degrades glycosaminoglycans and hyaluronic acid, with subsequent increases in tissue permeability and dispersion of extravasated agent.11,14 Hyaluronidase has been used for extravasation by etoposide, taxanes (ie, paclitaxel, docetaxel, and cabazitaxel), and vinca alkaloids.11 Although hyaluronidase is recognized as therapeutic for extravasation, there is much inconsistency with regard to proper technique and dosage. Additionally, there is a dearth of controlled, nonanecdotal studies proving its efficacy.
Rat studies have shown hyaluronidase to be effective at reducing the wound size and healing time in vinorelbine-induced extravasations.35 In 1994, hyaluronidase was also effective at preventing necrosis in 7 patients with accidental vinca alkaloid extravasation.36 Despite the poor evidence-based strength of recommendation, it is worth noting that the manufacturers of vinblastine indicate the use of hyaluronidase if extravasation occurs.37,38
Recent guidelines, especially for chemotherapeutic extravasations in adults, recommend a dosage of 150 units of hyaluronidase.30 However, dosage varies among institutions. For Amphadase (Amphastar Pharmaceuticals, Rancho Cucamonga, Calif.), Hydase (Akorn, Lake Forest, Ill.), and Hylenex (Baxter Healthcare Corporation, Deerfield, Ill.), vials contain 150 units/mL, which do not need further dilution.30 Vitrase (ISTA Pharmaceuticals, Irvine, Calif.) contains 2 mL of 200 units hyaluronidase, which should be further diluted in a 3:1 ratio of vitrase to normal saline (0.75 mL of vitrase solution with 0.25 mL of normal saline). Hyaluronidase (150 unit in 1 mL) should be administered through five 0.2 mL subcutaneous injections into the extravasation site.
For pediatric patients, it has been shown that the administration of 15 units of hyaluronidase is effective to resolve the extravasation.19 This dilution is achieved with 0.1 mL (150 unit/mL) hyaluronidase solution with 0.9 mL of normal saline, yielding the desired 15 units/mL for injection. The administration should be done immediately, with benefit seen when given within 3 hours of insult. In pediatric patients or infants, a 27–30 gauge needle is used to inject five 0.2 mL injections of hyaluronidase around the infiltration site in a circular pattern.19,30,39
Dexrazoxane [Zinecard (Pfizer, New York City), Savene and Totect (Clinigen Group Plc, Burton-on-Trent, United Kingdom)] is an FDA-approved local therapy for anthracycline (daunorubicin, doxorubicin) extravasation,11 which commonly results in severe tissue damage. Its mode of action is not well understood.11,40 Two prospective clinical trials, TT01 and TT02, were conducted to determine the efficacy and tolerability of treatment with dexrazoxane [Savene (Clinigen Group Plc, Burton-on-Trent, United Kingdom)]. These studies, unlike other extravasation studies, used fluorescence biopsies to objectify the diagnosis of extravasation.41 Fifty-four patients were confirmed to have anthracycline extravasation. The 54 patients underwent dexrazoxane treatment: 1,000 mg/m2 within 6 hours of insult, 1,000 mg/m2 24 hours after initial treatment, and 500 mg/m2 48 hours after initial treatment.41 Of the 54 patients receiving treatment, only 1 patient required a surgical intervention, an efficacy rate of 98%.41,42 In addition, over two-thirds the patients had no resultant delay in chemotherapeutic treatment secondary to soft-tissue wounds.41,42
Indication for dexrazoxane administration is extravasation of more than 5 mL of an anthracycline drug.9 It is contraindicated in the following patient populations: less than 18 years old, hepatic or renal insufficiency, recent inoculation with a live vaccine, and patients receiving phenytoin.9,43 It may also be teratogenic and should be avoided during pregnancy.44
The treatment consists of a 3-day course of IV dexrazoxane.45 The first dose of 1,000 mg/m2 is ideally administered as soon as possible, followed by 1,000 mg/m2 on day 2, and 500 mg/m2 on day 3.15,43,45
Concomitant administration of dimethyl sulfoxide (DMSO) is not recommended,15,43,46 as this has been associated with an increased occurrence of wounds.43
DMSO is a topical organosulfur solvent that increases skin permeability and, therefore, augments absorption and subsequent dispersion of the extravasated agent,11,30,47 and functioning as a free-radical scavenger.11 Ninety-nine percentage of DMSO is applied topically and may improve outcomes for smaller anthracycline extravasations. It was shown to be effective in resolving anthracycline extravasation in a prospective pilot trial of 20 patients. No patient required surgical intervention or had lesion formation.48 However, there is a lack of evidence using objective fluorescence biopsy data, and thus routine use in anthracycline extravasation remains controversial.47 However, DMSO in conjunction with cold compresses remains the most common acute therapy minor anthracycline extravasation, particularly if dexrazoxane is not available.11
DMSO should be implemented within the first 10–25 minutes of extravasation,9 while minimizing exposure to unaffected skin, followed by hydrocortisone if erythema is present,9 and then a cold compress. This process should be repeated every 2 hours for the first day, after which the frequency is reduced.9
Sodium thiosulfate functions as an additional target for alkylation and can hypothetically neutralize certain vesicants, specifically mechlorethamine (nitrogen mustard, no longer commercially available) or concentrated cisplatin.49–51 However, while many providers report the use of sodium thiosulfate, no randomized clinical trials have been conducted on its efficacy.51
When administered, sodium thiosulfate is injected subcutaneously in a pinwheel fashion around the affected tissue. Four to 8 mL of 10% sodium thiosulfate is mixed with 6 mL of sterile water.50 Two milliliter of sodium thiosulfate solution is injected for every milligram of mechlorethamine or 100 milligrams of cisplatin infiltrated.
The Gault Method of saline washout for extravasation injuries was first described in 1993.26 This method involves early saline washout with subsequent liposuction via a small incision. Forty-four of the 96 patients studied underwent early washout. Eighty-six percentage healed with no soft tissue loss compared with 15% in the late referral group. In areas with less subcutaneous fat, Gault describes injection 1 unit of hyaluronidase. This is followed by making 4 small incisions surrounding the extravasated area. Finally, the extravasation area is flushed with normal saline, resulting in irrigation of subcutaneous tissue and efflux through the previously placed incisions.26
In the event of tissue necrosis, the wound should be dressed in a manner to promote a moist, clean, and warm environment, while removing excess exudate.52,53 Eschar and necrotic tissue can impair reepithelialization and strong consideration should be given to debridement once the extent of tissue death has demarcated.54 Plain gauze (wet to dry dressings), while beneficial in debriding the wound bed on removal, can also traumatize viable healthy tissue, be painful, and needs frequent dressing changes to be effective. Nonadherent dressings [ie, Xeroform (Tyco Healthcare/Kendall, Mansfield, Mass.) and Adaptic [Johnson and Johnson, Somerville, N.J.)] can maintain a moist environment in epithelializing wounds and reduce pain with dressing changes, however should be changed daily to prevent them from drying and traumatizing the tissue bed on removal. Hydrocolloid dressings [DuoDERM (Convatec, Bridgewater, N.J.), Exuderm (Medline, Havre de Grace, MD), Comfeel (Coloplast, Minneapolis, Minn.), etc] can absorb mild amounts of exudate, maintain a moist environment, and minimize skin trauma with dressing changes. They have been shown to be of benefit in the neonatal population.55 Wounds with higher degrees of exudate may require more absorptive dressings such as alginates or hydrofibers.
In the majority of instances, conservative management is successful, as only 1 in 3 vesicants results in ulceration.56 Surgical management may become indicated if soft-tissue necrosis develops. Healing capability is typically impaired due to a lack of granulation tissue and restricted epithelial ingrowth resulting in ulcer progression.56 In patients undergoing chemotherapeutic treatment, open wounds may present an increased infection risk and delays in treatment. A discussion between medical oncologists and the surgical team is critical to determine the optimal treatment course and timeframe for the patient.
Debridement (with or without reconstruction) is indicated if extravasation results in continuous pain (persisting for 1–2 weeks), persistent ulceration, or full-thickness skin necrosis.9,11,14,15,46,57 Fasciotomy is the treatment of choice if compartment syndrome develops.6,41
Iatrogenic injuries secondary to intravenous extravasation are commonplace in hospitals. In severe cases, limb loss is a potential consequence of poor or delayed management. Nursing algorithms for management of extravasation injuries are usually directed toward consultation of a wound care team immediately after identification, who may implement local interventions in the appropriate time-sensitive manner. Hospitals without a dedicated wound care team trained in these interventions will often default to plastic surgical consultation, making an understanding of available interventions essential to the initial evaluation and management of these injuries. Guidelines for the treatment of extravasation injuries facilitate decision making, given their time-sensitive nature. Appropriate immediate management may reduce further damage, limb loss, and even avoid potential litigation. Although there is no standardized protocol for extravasations injuries, a proposed treatment algorithm is shown in Supplemental Digital Content 1.
The goal of this article was to provide plastic surgeons and trainees with a comprehensive overview of the acute management of intravenous extravasation injuries. Our hope is that this will serve as an effective resource for caregivers treating acute extravasation injuries (See figure, Supplemental Digital Content 1, which displays the treatment algorithm, http://links.lww.com/PRSGO/A724). Though the decision for surgical versus nonsurgical management is often a clear one for plastic surgeons, local interventions, and therapies are often indicated and under-utilized in the immediate postextravasation period. Thorough knowledge of these interventions should be a basic requirement in the armamentarium of plastic surgery consultants.
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Supplemental Digital Content
Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.