Which complication involves the entry of an intravenous solution containing a Vesicant drug into the subcutaneous?

Extravasation is a universal risk of intravenous (IV) vesicant administration. Appropriate precautions can reduce the risk but not eliminate it. The terms extravasation and infiltration are often used interchangeably in the literature, but the 2016 Infusion Therapy Standards of Practice (the Standards)1 defines extravasation as “inadvertent infiltration of vesicant solution or medication into the surrounding tissue,”1(pS149) whereas infiltration is the “inadvertent administration of a nonvesicant solution or medication into surrounding tissues.”1(pS150) A vesicant is an agent capable of causing tissue damage when it escapes from the intended vascular pathway into surrounding tissue. Vesicant identification and consensus treatment recommendations existed as early as 19792 for cytotoxic vesicants, but it is only in recent years that extravasation injury from noncytotoxic vesicants has begun to receive similar attention. In 2017, the Infusion Nurses Society (INS) Vesicant Task Force published an evidence-based list identifying noncytotoxic vesicants,3 but treatment modalities were outside the scope of that review. This article summarizes the evidence supporting treatments for noncytotoxic vesicant extravasations and contains recommendations to aid clinicians in making timely, evidence-based treatment decisions.

BARRIERS TO APPROPRIATE AND TIMELY TREATMENT

A calcium extravasation was the impetus for seeking evidence-based treatment recommendations for noncytotoxic vesicant extravasations. Every source reviewed had different lists of noncytotoxic vesicants and varying recommendations and reasoning for proposed treatments. The lack of consensus in the literature contributes both to undertreatment and inappropriate treatment of extravasations. In the case of extravasation injury, the cost of overtreating is minimal. The antidotes are relatively inexpensive, easy to prepare, and cause minor if any discomfort to the patient. In contrast, the cost of undertreatment can be hospitalization, surgical intervention, and permanent cosmetic and functional defects. Identified barriers to receiving appropriate, timely treatment include delayed recognition, unknown treatment options, lack of or inconsistent evidence supporting a treatment approach, and unknown or uncertain vesicant status of the medication.

Delayed Recognition

Despite recommendations in the Standards1 to assess vascular access devices for signs and/or symptoms of infiltration and extravasation before each infusion and on a regular basis, some extravasations are recognized after irreversible damage has occurred, limiting the efficacy of intervention options. Loth and Eversmann4 proposed the concept of a necrosis interval to guide therapy decisions. The necrosis interval is the time from extravasation until irreversible tissue damage occurs, and it varies for each vesicant. If the offending agent is counteracted or removed within the time interval, then necrosis is prevented. The necrosis interval has not been determined for every vesicant. However, because the interval can be quite short, for example 4 to 6 hours for vasopressors, extravasation should be considered a medical emergency requiring time-sensitive treatment. Recognition of extravasation outside the necrosis interval may preclude treatments that would prevent or reduce damage and instead necessitate damage control.

Unknown Treatment Options

To date there are no published articles that comprehensively describe the evidence supporting or refuting a wide variety of treatments for noncytotoxic extravasations. Even for treatment methods with documentation of efficacy, when confronted with drug shortages affecting first-line options such as phentolamine, second-line treatment options have not been as well documented.

Uncertainty as to Appropriateness of Treatment Options

Every extravasation is unique. No two will have identical factors influencing the extent of injury or treatment decisions. Both patient- and incident-specific factors influence treatment decisions. These factors can include age, weight, comorbidities, communication barriers, skin integrity, site of extravasation, anatomic anomalies, care setting, response to current treatment, timing of recognition, and, perhaps most importantly, the identity, amount, and concentration of the vesicant. With so many factors influencing treatment and prognosis, it may seem difficult or even impractical to apply evidence from one extravasation to another.

Despite the unique nature of each extravasation, all are identical in that the patient's tissues have inadvertently been exposed to a toxic substance. Tissue damage will occur unless the vesicant's toxicity and mechanism of tissue injury can be eliminated or reversed. Thus, extravasation treatments are generalizable when the mechanism of tissue injury and method to eliminate or reverse it are considered. Large, multicenter, randomized, double-blind, head-to-head, or placebo-controlled trials are the gold standard in evidence-based medicine. This level of evidence will never exist for extravasation, because ethical considerations preclude purposefully inflicting an extravasation on humans to test potential remedies. Perhaps, as a result of the varied nature of extravasations, the published recommendations and reported management of extravasations are just as varied. Conflicting recommendations and case reports describing a variety of treatment options have sometimes resulted in inappropriate therapy choices, such as applying cold compresses (instead of dry, warm compresses) to a norepinephrine extravasation. Applying reported or recommended treatments from one case to another should be done in the context of the mechanism of tissue injury and whether the proposed treatment is likely to eliminate or reverse the toxic potential of the vesicant.

Unknown or Uncertain Vesicant Status

Noncytotoxic vesicants are reported in many disparate lists. Even with all the evidence available, however, there are some medications that likely are vesicants but lack confirming evidence. These could include lower potency vesicants, those with a weaker propensity for causing tissue injury, or recently developed medications. Medications reviewed and ultimately excluded as noncytotoxic vesicants by the INS Vesicant Task Force3 (mostly because of insufficient evidence), as well as infiltration of any medication not yet identified as a vesicant, may warrant extravasation treatment if symptoms of extravasation occur. A medication may be a vesicant although it is not yet recognized as one.

LITERATURE SEARCH AND METHODOLOGY FOR EXTRAVASATION MANAGEMENT IDENTIFICATION

The Standards recommends that “each facility should reach a consensus on what medication is considered to be a vesicant and irritant based on their internal formularies” and “identify the vesicant nature of antineoplastic and noncytotoxic medications prior to administration and be prepared to use the correct antidote treatment for each medication.”1(pS98)

From published lists, 86 purported vesicants were identified. Inclusion in the vesicant list required either: (1) reports in literature or from manufacturer of tissue injury upon extravasation or (2) adverse effects or warnings in secondary drug information sources such as Micromedex or Lexicomp consistent with a vesicant along with a valid proposed mechanism of tissue injury.

Of the 86 purported vesicants vetted, 45 drugs met our inclusion criteria. This review, which began in August 2016, was bolstered in January 2017 when the INS Vesicant Task Force published an evidence-based list of noncytotoxic vesicants.3 Of 42 purported vesicants vetted by Gorski et al,3 25 were classified as vesicants. The other 17 were indeterminate at the time due to inconclusive or conflicting data. Based on more recent case reports, 3 of the 17 indeterminate vesicants (gentamicin, immune globulin, and propofol) met our first vesicant criteria. Of the remaining 14 indeterminate vesicants, another 8 met our first inclusion criteria (aminophylline, amphotericin, ampicillin, doxycycline, lorazepam, metronidazole, penicillin, and valproate). We had reviewed 44 purported vesicants that the INS Vesicant Task Force did not review, 4 of which met our first criteria (digoxin, lipids, methylene blue, and phosphate salts) and 5 of which met our second criteria (conivaptan, dantrolene, diazepam, esmolol, and etomidate). Radiographic contrast material is excluded from our recommendations due to the unique nature and scope of contrast extravasations. Other exclusions included antineoplastic vesicants, products not recommended for IV use, extravasations not involving skin or soft tissue (eg, intraperitoneal), and products not available in the United States.

Aside from the US Food and Drug Administration (FDA)-approved antidote phentolamine, literature support for antidotes and thermal compresses is largely limited to case reports or case series. More than 1800 cases were included in this review, but for treatments short on published evidence, published articles with recommendations have also been included to support a consensus recommendation. Previously published recommendations represent the authors' opinion, description of local practice, or institutional guidelines.

The US National Library of Medicine holdings in the PubMed database were searched without beginning date restriction through February 15, 2020, using the search string “Extravasation of Diagnostic and Therapeutic Materials” [Mesh] OR “Extravasation” [Title] OR (Infiltration OR extravasa*) AND drug AND “Humans” [Mesh]. Of the 23,159 titles or abstracts screened manually, the full text of 257 articles was sought. Because of the inability to translate or unavailability of the full text, 14 articles were excluded from full-text review. On bibliography screening, the full text of an additional 226 articles was reviewed. Of the 469 articles reviewed, 331 articles were ultimately included in the review, and 138 were excluded for the following reasons:

1. Chemotherapy extravasations (6 articles)
2. Vesicant not identified (25 articles)
3. Infiltration of irritant, not of a known vesicant (15 articles)
4. Adverse effect without extravasation, that is, a systemic effect (21 articles)
5. Norepinephrine untreated or phentolamine monotherapy, already FDA approved (15 articles)
6. Vesicant unavailable in the United States (mezlocillin/sulbactam, metiamide, toluidine blue) (3 articles)
7. Noncontributory in either recommendations or cases (45 articles)
8. Anatomically distinct extravasation (eg, intra-arterial or neonatal umbilical vein) (8 articles). For a thorough list of other articles describing anatomically distinct extravasations, see Appendix 2 of Corbett et al.5

In conversation with J. Friedman, MD (July 11, 2019), and written communication with J. L. Thigpen, RNC, MN (November 1, 2019), V. Boyar, MD (November 2, 2019), and J. C. Schie, MS, OTR/L (November 18, 2019), we were able to clarify which drug extravasated in several previously published cases.6–9 Medication prescribing information was also used. Pertinent landmark animal case studies were also reviewed.

MECHANISMS OF TISSUE INJURY

Vesicant classification by mechanism of tissue injury is useful in determining appropriate management to eliminate or reverse the toxic potential of an extravasate. The 4 widely recognized mechanisms of tissue injury are pH, osmolarity, vasoconstriction, and cytotoxicity. We propose absorption refractory as a new fifth mechanism of tissue injury.

Nonphysiologic pH

Physiologic pH is 7.35–7.45. Extreme pH exposure, typically defined as a pH of <5 or >9,10 can damage venous endothelium and increase risk of vessel rupture. When agents with extreme pH extravasate, they can cause damage in the same manner.11,12 Tissue destruction and vasoconstriction with resulting inflammatory response, edema, sloughing, and ulceration may result. Neutralization of extreme pH should not be attempted because of the potential for exothermic or gas-producing reactions that may exacerbate the injury.13

Osmolarity

Physiologic osmolarity is approximately 310 mOsm/L.14 Both hypotonic and hypertonic solutions can cause tissue damage by forcing fluid shifts into or out of cells. Hypotonicity causes fluid shift into cells, which can result in cell rupture. The generally accepted cutoff for hypotonicity and risk of hemolysis with IV infusion is <112 mOsm/L,15 whereas for hypertonicity and risk of being a vesicant the cutoff is >900 mOsm/L.16 Hypertonicity disrupts cellular ion transport and causes fluid shift from cells to the interstitial space, which may lead to swelling and compartment syndrome. Histopathology confirms, for example, that extravasation of 10% calcium chloride, which has an osmolarity of 2050 mOsm/L, is “a true ‘subcutaneous burn’ and as such involves both the overlying skin and the underlying fascia and skeletal muscle.”17(p155) High osmolarity vesicants, including phosphate and calcium, also present a precipitation risk. Calcium precipitation in soft tissues is called calcinosis cutis and can occur with or without accompanying necrosis.1,18–20

Vasoconstriction

Localized vasoconstriction attributed to extravasation can result in ischemia and necrosis by reducing blood flow. Vesicant exposed tissues are at risk from both chemically induced and mechanically induced vasoconstriction. Electrolyte solutions such as calcium and sodium, along with pharmacologic vasopressors such as dopamine and epinephrine, can chemically induce vasoconstriction. Large volume or anatomically trapped extravasations can mechanically induce vasoconstriction when the interstitial pressure is raised enough to overcome the venous pressure, blocking blood flow and even causing compartment syndrome.

Cytotoxicity

Cytotoxicity is primarily associated with antineoplastic drugs. For antineoplastic drugs, extravasation injury occurs as a result of the vesicant binding to the nucleic acids in the DNA of healthy cells in the tissue causing cell death. Other cytotoxic vesicants damage cells or tissues on coming into direct contact with them. The identity and treatment of antineoplastic vesicants have been published elsewhere and are outside the scope of this review.21

Absorption Refractory

Absorption refractory is a newly proposed mechanism of tissue injury whereby drugs with insolubilities or limited ability to be absorbed into the bloodstream persist in the extravasated space. The prolonged presence of lipids in the interstitial space has led to deep tissue necrosis, and propofol, often contained in a lipid carrier solution, seems particularly prone to causing necrosis and compartment syndrome because of its limited ability to disperse in the tissues and be absorbed into the bloodstream.22–36

MANAGEMENT RECOMMENDATIONS

Effective extravasation management requires early recognition of signs and symptoms and prompt implementation of appropriate clinical management strategies.1 Extravasation is unique, but the patterns of initial symptoms are commonly staged as first proposed by Millam in 198837 and validated in a pediatric population by Flemmer and Chan in 1993.38 Published iterations of this staging are used widely for patients of all ages. Strengths from multiple versions have been refined, and the resulting proposed staging recommendations can be found in Table 1.4–6,37–40 Extravasations of small volume with less potent vesicants are likely to fit into stages 1 or 2, whereas more potent vesicants and/or larger extravasated volumes will tend to reach stages 3 or 4. Once the necrosis interval has passed (which can be as short as 4 to 6 hours for vasopressors), the staging table is no longer relevant, and assessments should be made based on whether the injury is receding or advancing.

TABLE 1 - Extravasation Staging

Data from Loth and Eversmann,4 Corbett et al,5 Friedman,6 Millam,37 Flemmer and Chan,38 Baharestani,39 and Odom et al.40

Where treatment options have limited evidence supporting efficacy, clinicians must consider the potential benefits of the treatment and initiate those therapies where the benefits outweigh the risks. More invasive extravasation treatments are associated with greater risks, but they are also associated with faster onset and greater impact. Recommended initial treatment options ranked in order from least to greatest impact and risk are as follows: elevation, thermal therapy, antidote administration, saline flush out, and open incision with irrigation. Extravasation management for stage 1 and 2 injuries should begin with elevation and thermal therapy and advance to antidote administration at 30 minutes if the injury is not resolving. Because stage 3 and 4 injuries are unlikely to downstage with the impact of elevation and thermal compresses alone, antidote therapy should be initiated immediately.38 If the injury has not downstaged or is not resolving by 30 to 60 minutes after the initial antidote, consider repeating antidote administration or switching to alternative antidote until symptoms begin to resolve. If at any point it appears that antidote administration will not be sufficient to prevent extensive injury, consider immediately advancing to a saline flush out or open incision and irrigation.41,42 The level of treatment should be proportional to the level of injury and should err on the side of overtreatment when it comes to antidote administration, because the costs of antidote overtreatment are minimal when compared with the potential costs of undertreatment. The impact of elevation and thermal compress therapy on symptom resolution is small when compared with the impact of antidote administration or saline flush out.

For pH-mediated, osmolarity-mediated, and absorption refractory extravasations, the goal is to dilute the vesicant through absorption and dispersal, so the appropriate antidote is hyaluronidase. Cytotoxic vesicants with concentration-dependent toxicity can also be treated with hyaluronidase. Vasodilators, such as phentolamine, terbutaline, or nitroglycerin, should be used to counteract vasoconstriction, whether caused by a vasoconstrictor, chemical vasoconstriction, or mechanical vasoconstriction. Table 243–297 contains antidote recommendations for each noncytotoxic vesicant. Additional antidote and treatment evidence not definitively linked to a particular vesicant is presented in Table 3. 298–304

TABLE 2 - Antidote Recommendations for Noncytotoxic Vesicants

Abbreviations: FDA: US Food and Drug Administration, PFD: permanent functional deficit.

TABLE 3 - Case Series Not Linked to a Specific Vesicant

Abbreviation NICU, neonatal intensive care unit.

The clinical practice setting will influence which treatments are available. Initiate as much treatment as is indicated and possible. If the injury has not downstaged to level 1 with the maximum level of care the current setting can accommodate, clinicians should consider transferring the patient to a hospital with plastic surgery capabilities while there is still potential to prevent the damage rather than transferring the patient for debridement and skin grafting after the damage has occurred.

Overview of Treatments

The toxicity of vasoconstrictive vesicants can be reversed by vasodilator administration, but pH, osmolarity, and even to some extent cytotoxic vesicants have concentration-dependent toxicity. To dilute the vesicant to eliminate its toxicity, it must either be absorbed into the bloodstream or dispersed among interstitial fluids. Hyaluronidase facilitates both. An FDA-approved indication of hyaluronidase is as an adjuvant to increase the absorption and dispersion of other injected drugs.305 This can be used, for example, as a planned enhancement to localized analgesia, but with extravasation it is used as an unplanned rescue attempt to facilitate dispersion and absorption into the bloodstream from the extravascular space. The use of hyaluronidase for extravasation injury is not FDA approved and is therefore considered “off-label.”

Hyaluronidase facilitates absorption and dispersal of drugs and fluids by dissolving hyaluronic acid, one of the binders that holds soft tissue cell layers together and forms the dermal barrier. By loosening the layers from each other, fluid is able to flow freely between sheets of tissue. “The rate and extent of dispersion and absorption is proportionate to the amount of hyaluronidase and the volume of solution.”305p6 A 150-unit dose of hyaluronidase will facilitate the absorption of 1 L or more of subcutaneously administered fluid.305 In studying hyaluronidase for hypodermoclysis, Hallman et al306 used each pediatric patient as their own control, receiving subcutaneous fluids in both legs but hyaluronidase in only one leg. Without regard to bolus volume (range, 20–40 mL) or fluid type (saline or dextrose), hyaluronidase accelerated absorption in every measurable case (anatomy precluded measurement in 2 patients). On average, hyaluronidase accelerated absorption time to 84 minutes versus 214 minutes without hyaluronidase. In 2 cases in particular, skin tension decreased within only 2 minutes of hyaluronidase administration.306 The dermal barrier does not reform in full until approximately 48 hours later in a dose-dependent manner.305

Hyaluronidase is an effective mainstay of extravasation treatment. In 1950, Haire307 reported that the pain, swelling, and induration caused by extravasation of neoarsphenamine in one case and mapharsen in another resolved completely within 24 hours after treatment with 250 units of hyaluronidase. He reported that the amounts extravasated in these cases would normally have caused a painful induration lasting for weeks. Acceptance of hyaluronidase to treat extravasation injuries grew and was mentioned in surgical textbooks as early as 1953.308 Although ethical considerations preclude the study of hyaluronidase versus placebo for extravasation injury in humans, Zimmet309 demonstrated in rats that, after injection with 23.4% sodium chloride, hyaluronidase-treated rats had a decreased incidence of ulceration (50%) versus normal saline or water (80%). The average ulceration size in the normal saline and water groups was 2 to 3 times as large as in the hyaluronidase groups. Similarly, Laurie et al310 demonstrated in rabbits that after parenteral nutrition injection, rabbits receiving no treatment had ulcers on average 13 times as large as hyaluronidase-treated rabbits. After injection with calcium chloride, ulcer size in normal saline-treated and untreated rabbits was on average more than twice as large as hyaluronidase-treated rabbits. When hyaluronidase treatments in calcium chloride injected rabbits were delayed by 1 hour, the benefits remained statistically significant, but at 30 minutes, 3 hours, 6 hours, and 12 hours, hyaluronidase trended toward benefit but did not reach significance (P = .1, P = .3, P = .5, and P =.2, respectively). The authors theorized that the acute inflammatory phase at 30 minutes postextravasation inhibited the benefit of hyaluronidase and that the positive impact then began to wear off after the 1-hour mark. Timely administration of hyaluronidase can promote complete absorption of a vesicant before the necrosis interval is reached, thus preventing permanent damage.

The effect of hyaluronidase in the treatment of accidental extravasation is rapid and marked. The effect of hyaluronidase has been described as “immediate blanching of the overlying erythematous skin and dramatic decrease in swelling,”202(p246) that “within 5 minutes of hyaluronidase administration, the infant's foot developed a pinker hue and began to soften.”51(p187) “Within 30 minutes, the patient's pain lessened, erythema abated, and soft tissue swelling was noted to improve.”119(pp257,e1) More objectively, in 1 patient after only 15 minutes, the dorsalis pedis pulse that had been nonpalpable was again palpable,51 and in a second case after a repeat administration of hyaluronidase, the radial and superficial palmar pulses, which had been absent to auscultation, were once again present.202 Others have described the effect as “swelling and redness markedly decreased” over the 5-hour observation period and the patient's limb was normal sized again at 24 hours.118(pp886,e4) In the author's experience, a patient's intense itching and burning sensation from amiodarone extravasation completely resolved within 90 minutes of hyaluronidase administration without any adverse effects. Hyaluronidase is a highly effective, inexpensive therapy that can be administered with minimal discomfort.

Pharmacologic Antidotes

Hyaluronidase

For adult and pediatric patients, 15 units (up to 150 units) is typically administered subcutaneously in 5 divided doses of 0.2 mL each on the periphery of swelling like the points of a star. Repeat dosing every 30 to 60 minutes until desired effect is achieved. Total doses up to 450 units have been used without adverse effect.45,59

Sodium Thiosulfate

Calcinosis cutis treatment for adults is 12.5 g IV over 30 minutes and may increase gradually to 25 g 3 times per week.13,102 Sodium thiosulfate combines with calcium to create calcium thiosulfate, which has a solubility between 250 and 100,000 times greater than other calcium salts.311

For acute extravasation treatment and calcinosis cutis prevention, mice treated with 0.1 mL of 25% sodium thiosulfate intradermally after injection with 0.12 mL of calcium gluconate had reduced incidence of calcification versus untreated mice (13% versus 53%) and 100% resolution of all ulcerations by day 21 versus only 73% resolution in untreated mice.311

Phentolamine (α1 Antagonist)

For adult and pediatric patients 5 to 10 mg in 10 to 20 mL of normal saline is typically administered intradermally in 5 divided doses on the periphery of blanching like the points of a star. This may be repeated every 30 to 60 minutes until desired effect or patient experiences an intolerably low blood pressure. Half-life in the bloodstream is 19 minutes.285 Doses as low as 0.5 mg have been used initially in adults, and Zenk et al45 recommend 0.5 mg as the starting dose in neonates.257

Terbutaline (β2 Agonist)

For adult and pediatric patients, terbutaline 1 mg in 10 mL of normal saline is typically administered intradermally in 5 divided doses on the periphery of blanching like the points of a star.233 This may be repeated every 30 to 60 minutes until desired effect or patient experiences intolerable systemic effects, such as tachycardia or irregular blood pressure. The drug's half-life is 2.9 hours.312

Topical Nitroglycerin (Peripheral Vasodilator)

Apply 1 inch topically for adults and 4 mm/kg for neonates to affected area every 8 hours as needed until symptoms resolve.242,245

Nonpharmacologic and Supportive Therapies

Other than thermal therapy with warm or cold compresses, the use of supportive therapies is outside the scope of this review. They are presented merely to illustrate which therapies could be considered without a recommendation for or against their use.

Elevation

Yucha et al313 tested intentional 5-mL infiltrations of 0.45% saline and 3% saline when the infiltrated arm was kept at the level of the heart versus elevated by 4 inches. They found no difference in pain scores, induration size, or infiltrate volume. This could have been attributed to the low volume of infiltrate or the small difference in elevation angle. Elevation may have a greater impact with a larger volume of infiltrate, for example 50 mL, or with a steeper angle of elevation, which has been used in neonates.300

Warm and Cold Compresses

Compresses can be applied at 15-minute intervals 4 times daily, although continuous use of up to 72 minutes on initial extravasation has been reported.314 Cold compresses should be used when the goal is to localize and limit the spread of the vesicant to mitigate the damage, such as with cytotoxic vesicants.50 Cold compresses should be used to treat extravasations of valproate, because the proposed mechanism of tissue injury is toxicity to skin structures.232 Warm compresses in conjunction with vasodilatory antidotes (phentolamine, terbutaline, and nitroglycerin) should be used for extravasation of vasoconstrictive vesicants where the goal is to increase circulation. For pH-mediated, osmolarity-mediated, absorption refractory, and even some cytotoxic concentration-dependent vesicants, the goal is to disperse and absorb the vesicant, so warm compresses should be used along with the antidote hyaluronidase.13,50 Vesicants containing fats, including 3-in-1 parenteral nutrition and the absorption refractory vesicants propofol and lipids, will experience improved absorption and distribution with warm compresses because of improved solubility and decreased viscosity of fats with increased temperature. “Use of dry heat in conjunction with hyaluronidase works synergistically to increase blood flow and disperse the extravasated drug.”1(pS100) Hastings-Tolsma et al314 demonstrated that warm compresses are effective at aiding in dispersion of infiltrated fluids, whereas cold compresses tended to keep the fluids trapped. Eighteen patients had 5 mL purposefully infiltrated; 6 with 0.45% saline, 6 with 0.9% saline, and 6 with 3% saline. At 12, 42, and 72 minutes postinfiltration, the 9 patients with warm compresses had statistically significantly lower infiltrate volumes remaining (P < .001) versus the 9 patients with cold compresses (3 in each concentration group). Thermal compress therapy is not without risks and should be performed carefully.236,315 See Table 4 for thermal compress recommendations.316–332

TABLE 4 - Thermal Compress Recommendations for Noncytotoxic Vesicants

aAuthors' recommendation.

Physical Massage or Compression Therapy

To manually aid in fluid dispersion and reduce tissue pressure, physical massage can be used, or an inflatable splint can be placed on a neonate and inflated for a portion of every hour to physically disperse infiltrated fluid that is anatomically trapped.333,334

Localized Steroid Therapy

Topical or locally injected steroids have been reported with mixed results. Ahn et al335 found in rabbits that triamcinolone therapy seemed to reduce the reaction but was unable to prevent calcinosis cutis. Compaña et al311 conversely found that, in mice, triamcinolone therapy actually worsened the extent of the reaction.

Antimicrobial Therapy

Topical and systemic preventive antimicrobial therapy have been reported. Silver sulfadiazine cream can be used, because extravasation is a chemical burn. Secondary bacterial infections of damaged tissue have been reported and treated accordingly with topical or systemic antimicrobial agents as indicated.

Saline Flush Out/Irrigation

A highly effective method of physically removing the vesicant is through multiple surgical incisions along with placement of a catheter to administer a physiologic saline flush out and perform aspiration that is similar to liposuction.41 Saline flush out has become so common in London that advance practice nurses are performing the procedure as opposed to a plastic surgeon.336 Other variations from this method include open incision and irrigation, incisions and drain insertion, incisions with mechanical pressure from gentle massage, or saline flush out without aspiration.13,42,139a,142,167

Once a wound develops, consultation with a wound care clinician is advisable, because a multitude of different wound care strategies have been reported.6,9,139a,173,228,323,333,337–340

DISCUSSION

In the recognition and treatment of an extravasation injury, there are 4 possible outcomes:

• Treatment indicated–treated
• Treatment indicated–untreated: error
• Treatment not indicated–treated: error
• Treatment not indicated–untreated

The potential errors are either overtreatment, if treated without indication, or undertreatment, a lack of treatment when indicated. In the balance of how aggressively an institution manages extravasation injuries, they will tend to overtreat or undertreat extravasations. Because of the unique nature of each extravasation, determining the appropriate level of treatment is challenging. Whether extravasation treatment is indicated is difficult to assess initially. In most reported cases, the extent of injury was far greater than it first appeared. Some common reasons for this are as follows: (1) signs and symptoms occur internally, not just externally where visible; (2) physical signs of damage may be masked by other symptoms; (3) uncertainties in timing and volume of the extravasation; and (4) delayed presentation of symptoms (eg, calcium deposition). Imaging such as x-ray, magnetic resonance imaging, ultrasound, and gallium uptake bone scan (in cases of calcinosis cutis) can be used to estimate the volume of extravasation or the extent of internal injury, but in assessing whether to treat in the absence of compelling evidence either way, the cost of overtreatment or undertreatment must be considered.61,104,138,160

Overtreatment of extravasation injury incurs minimal cost, because the antidotes are inexpensive and are well tolerated. Initial undertreatment of extravasation has caused prolonged hospitalization of up to 55 days.72 The extravasation injury is often more severe than the primary diagnosis. Morbidity and mortality on the magnitude of debridement of necrotic tissue, skin grafting, limb amputation, and even death from fungal meningitis following a parenteral nutrition extravasation have all been reported.64,162,167,171 Extravasations that appear to be managed appropriately but are undertreated may present later with unforeseen consequences, such as secondary necrotizing fasciitis, limb deformations from prematurely fused growth plates or fibrin deposition, scalp skin grafting with a residual bald spot, an ossified mass inhibiting foot flexion, or retinal detachment from secondary infection.64,68,341–344 Morbidity can also be accompanied by litigation.218 Not every extravasation injury requires treatment, but in the decision between potentially committing an overtreatment error versus an undertreatment error, generally the safer decision for the patient and for the clinician is to treat.

For treatment of large-volume infiltrations of medications that are not known vesicants, hyaluronidase should be considered. It has the potential to prevent tissue injury or compartment syndrome as “it can reduce pressure necrosis from mechanical compression of tissues by large amounts of IV fluids trapped in a limited tissue space.”45(p295) Infiltrations of nonvesicant medications that are large in volume compared with the size of the anatomic infusion site can cause vesicant-like damage. In very low birth weight infants, the line between irritant and vesicant blurs, because most infusion volumes are large compared with their very small size, so large-volume extravasations of any fluid in these patients should be treated with hyaluronidase.345

Treatment bias exists in the extravasation body of literature. Less severe extravasations are less likely to receive an antidote but are also more likely to resolve on their own without necrosis, making it appear that antidotes are unnecessary to facilitate healing without necrosis. More severe extravasations are more likely to receive an antidote but are also more likely to result in necrosis or permanent functional deficit, making the antidotes appear ineffective because they were unable to prevent necrosis. The efficacy of an antidote is demonstrated when antidote administration mitigated the catastrophic damage that could have resulted or altogether prevented damage that would have occurred. Because there is no controlled comparator, the damage that might have occurred if not treated can only be presumed based on cases where no antidote was administered. Without standardized severity reporting, appropriately comparing results of antidote-treated cases with untreated cases is difficult if not impossible.

Reporting and observation bias are also seen in extravasation literature. Cases that resolved spontaneously or are similar to previously reported cases are generally not considered worthy of reporting. Alternatively, case series targeting the safety of a peripheral infusion of a vesicant are watching for extravasations to happen and so are likely to catch them earlier, resulting in a low incidence of mild extravasation injuries. This may misrepresent the true incidence and severity of extravasations.

CONCLUSION

Extravasation injury is an established risk of IV vesicant administration. Preventative measures can decrease the risk but not eliminate it, so clinicians should be prepared to treat extravasation injuries in a time-sensitive, evidence-based manner. Treatments are based on the vesicant's mechanism of tissue injury. Cytotoxic vesicants with concentration-dependent toxicity can be treated with warm compresses and hyaluronidase. If the potency of the cytotoxic vesicant cannot be mitigated through dilution, the most appropriate therapy might be cold compresses with strong consideration of saline flush out. The antidotes for vasopressor extravasations are phentolamine, terbutaline, or nitroglycerin. For pH-mediated, osmolarity-mediated, and absorption refractory extravasations, the antidote is hyaluronidase. Warm compresses should be used for vasopressor, pH-mediated, osmolarity-mediated, and absorption refractory vesicants. Future study regarding absorption refractory vesicants to better characterize this newly proposed mechanism of tissue injury would help clinicians better understand this pattern of tissue damage and could add support to treatment recommendations.

Because the body of extravasation literature is subject to multiple biases, more evidence must be gathered in a standardized way before extravasation recommendations can rely solely on evidence without the need for supporting consensus recommendations. In scenarios similar to extravasation injury where ethical considerations preclude clinical trials, like fetal drug exposure, evidence has been gathered in registries. Registries can be managed by a health system–based research organization, as part of a clinical trial, by a drug manufacturer or joint manufacturer effort potentially as part of a Risk Evaluation and Mitigation Strategy, by a nonprofit research organization or by a professional organization (https://www.fda.gov/science-research/womens-health-research/list-pregnancy-exposure-registries). The American College of Radiology has a registry for IV contrast extravasation, but no registry covers any other noncytotoxic extravasations (https://www.acr.org/-/media/ACR/Files/Registries/NRDROverview.pdf). According to poison control operatives, poison control advises patients and clinicians on accidental epinephrine autoinjector exposure management and advises clinicians for noncytotoxic extravasations on a regular basis (personal communication, December 3, 2019). When reports of extravasation accumulate, the evidence-based recommendations will become even more robust. Outside of a registry, adverse effects can and should be reported within the United States to the FDA MedWatch. Because the scope of MedWatch contains any serious adverse effect, the required details are not tailored specifically to extravasation injury like a registry reporting form could be. Registry data collected and published by the task force of a professional organization have the greatest chance of producing the requisite case information in the volume necessary to support evidence-based recommendations. The authors hope that as clinicians follow the recommendations contained in this document, the registry could support or refute and refine these recommendations to provide a more robust set of evidence-based noncytotoxic extravasation management recommendations.

ACKNOWLEDGMENTS

The authors would like to thank Jan Rice, MLS, AHIP, and Terri Raburn, MLIS, for their expert assistance in the literature search and citations and Lisa Gorski, MS, RN, HHCNS-BC, CRNI®, FAAN, for her encouragement, support, and assistance in manuscript preparation.

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