Extravasation of Noncytotoxic Drugs

Acyclovir

Acyclovir is an antiviral nucleoside analog effective in the management of herpes simplex virus, varicella zoster virus, and cytomegalovirus. Intravenous acyclovir has a pH of 11 and an osmolality of 278 mOsm/kg at a concentration of 7 mg/mL in dextrose 5%. ¹³ Only 1 case of acyclovir extravasation has been reported to date. De Souza and Shibu ¹⁴ describe a 51-year-old man who sustained an acyclovir extravasation injury in his left hand during treatment for ophthalmic herpes zoster. No extravasation treatment was administered when the event occurred. The patient was readmitted 3 months later for treatment of left-hand cellulitis. There was no evidence of tissue necrosis or ulceration. The authors suggest the injury to be severe chemical inflammation caused by the alkaline acyclovir solution. The wound was managed with physical therapy and compression garments.

Amphotericin

Amphotericin B is a broad-spectrum antifungal agent. Amphotericin B has a pH between 5 and 6 and an osmolality of 256 mOsm/kg. ¹³ Although the vesicant potential should be low based on these drug-specific properties, it is unclear why amphotericin B causes thrombophlebitis and chemical irritation when extravasated. ¹⁵ There is only 1 report of amphotericin B extravasation. Olson and McCoy ¹⁶ describe a case of inadvertent extravasation of 40 mg of amphotericin B in 250 mL of dextrose into the right antecubital area. At the end of the 3-hour infusion, the patient reported symptoms of pain and swelling. The patient was instructed to elevate the arm. Cold compresses were used initially but then were switched to warm compresses by day 2. All supportive care was discontinued on day 3. The area of extravasation completely resolved after 5 months. In this case, the proposed mechanism of tissue damage from extravasation was mechanical compression as a result of increased fluid in the interstitial space.

Metronidazole

Metronidazole is an antimicrobial agent active against anaerobic organisms, Clostridium difficile, and protozoa. The intrinsic properties of intravenous metronidazole, including a pH of 5.5 and an osmolarity of 310 mOsm/L, would not identify metronidazole as having the potential to cause tissue necrosis. To date, there is only 1 published case of metronidazole extravasation. Bharani et al ¹⁷ describe the development of gangrene in nearly all fingers after 50 mL of metronidazole extravasated into the dorsum of the right hand, which was initiated for symptoms of fever, diarrhea, and worsening abdominal distension. In this case, treatment with aspirin, pentoxifylline, and nifedipine did not prevent gangrene formation. ¹⁷

Nafcillin

Nafcillin is a β-lactam penicillin that is active against streptococci and staphylococci infections through its ability to interfere with bacterial cell wall synthesis. Tissue injury caused by nafcillin extravasation and phlebitis has been documented in a handful of case reports.^18-21 However, the mechanism of cell damage is not entirely known. It is neither acidic nor basic, with a reconstituted pH ranging from 6 to 8.5. ¹³ In case reports, the final concentrations of nafcillin were well below the maximum recommended concentration of 64 and 71 mg/mL in dextrose 5% and 0.9% sodium chloride, respectively. However, animal studies have shown that tissue necrosis may occur with infusions diluted to concentrations per manufacturer’s guideline. ¹⁸ The only antidote reported to have been used for the management of nafcillin extravasation is hyaluronidase. By facilitating the diffusion of extravasated fluids into surrounding tissue, hyaluronidase allows for rapid absorption and minimizes further tissue damage. Other suggested treatment options include cold compresses and sulfadiazine silver cream.^18,19

Oxacillin

Oxacillin, a β-lactam penicillin, is closely related to nafcillin and used mainly to treat infections related to Gram-positive organisms. Oxacillin has a pH of approximately 4.8 to 5.7 and an osmolarity ranging between 326 and 379 mOsm/kg per 1 g of oxacillin in 50 mL of sodium chloride 0.9% or dextrose 5%. ¹³ These properties do not lend themselves to oxacillin being extremely caustic to venous epithelial cells. There is only 1 published report of oxacillin extravasation. In this case, oxacillin was administered through a left antecubital vein. Extravasation was noticed after the second dose when the surrounding area of infusion was notably red and painful. The lesion progressively worsened to an 8 × 6 cm² area with tissue necrosis. Given the limited extent of extravasation, the course of treatment followed supportive care with topical steroids, cold compresses, and silver sulfadiazine dressings instead of surgical intervention. The area eventually healed leaving behind a small scar. ²²

Vancomycin

Vancomycin inhibits cell wall synthesis and is effective against Gram-positive organisms such as nosocomial staphlyococci and enterococci. Because of its poor oral bioavailability, vancomycin is primarily administered intravenously, except in the treatment of Clostridium difficile. Vancomcyin solution is acidic (pH of 2.5-4.0) ¹³ and hyperosmolar (328 mOsm/L) ¹³ when concentrated to 10 g/L for central venous catheter administration. ¹³ Such an acidic and hyperosmolar solution has the potential to be a vesicant when administered through a peripheral line. ²³

A case published by Hoelen et al ²⁴ described the development of an ischemic lesion at the dorsum of the patient’s left foot 48 hours after the start of vancomycin therapy. Vancomycin was immediately withdrawn, and the lesion resolved without any further intervention. Bohm and Wong ²⁵ reported a case of linear IgA bullous dermatosis that occurred in a 72-year-old woman after the majority of a 1-g intravenous dose of vancomycin extravasated into her right upper arm. The lesions were described as vesicles accompanied by redness, swelling, and hyperpigmentation. The site of extravasation gradually improved after local wound care and arm elevation.

Amiodarone

Amiodarone is one of the most widely used anti-arrhythmic agents available and is effective for a variety of arrhythmias. In emergent situations, amiodarone is given undiluted through a peripheral intravenous line. Amiodarone has a pH of 4.08 and contains polysorbate and benzyl alcohol as part of the diluent. ¹³ There is only 1 known published case report of amiodarone extravasation to date. In the setting of cardiac arrest, an amiodarone bolus of 300 mg followed by a 900-mg infusion over 23 hours was administered through a peripheral line. The authors attribute the development of severe blistering and skin necrosis on the right forearm approximately 1 day after the start of infusion to amiodarone extravasation. Treatment with hot or cold packs and topical steroid cream were recommended by the manufacturer. ¹¹

Dobutamine, Dopamine, Epinephrine, and Norepinephrine

Dobutamine, dopamine, epinephrine, and norepinephrine are vasoactive agents widely used for cardiovascular syndromes. In emergent settings secondary to hemodynamic instability, administration of vasopressors may be limited to a peripheral line because of lack of a central line access. At varying degrees of potency, all 4 agents stimulate α-adrenergic receptors and are, therefore, considered to be effective vasoconstrictors. ²⁶ Extravasated vasopressors can propagate cell damage by inducing venous and arterial vasospasms and causing disruption to vein wall integrity. ²⁷ All 4 agents are considerably acidic, with dopamine having a pH of about 3.3, epinephrine a pH of 2.2 to 5.0, norepinephrine a pH of 3.0 to 4.0, and phenylephrine a pH of 3.0 to 6.5. ¹³ It is widely known that extravasation of these vasopressors can cause significant tissue damage, skin sloughing, and dermal necrosis.^5,27-44 This is true for dopamine even at low doses, where there is minimal α-adrenergic activity. ³⁰

Phentolamine is the only FDA-approved antidote for the treatment of α-adrenergic agonist drug extravasation. As an α-receptor antagonist, phentolamine competitively works against circulating catecholamines and is effective in partially reversing ischemic changes caused by dopamine-induced extravasation. It is most effective when injected subcutaneously into the surrounding area within 12 hours of extravasation. Negligible side effects have been reported with the use of phentolamine.^31-34,45

In situations when phentolamine is unavailable, terbutaline, a pure β₂-agonist, has been reported to be successful in reversing local vasoconstriction. The vasodilatory effect of terbutaline attenuates vasoconstriction caused by α₁-agonism. Terbutaline 1 mg can be diluted to either a 1:10 concentration in normal saline for larger affected areas or 1:1 concentration for localized ischemia, such as in a finger. Terbutaline should be used with caution in patients with underlying cardiovascular disease because of the risk of arrhythmias and myocardial ischemia. ³⁵

Topical nitroglycerin has been reported to be effective in reversing ischemic changes of extravasated dopamine in situations where local injection of phentolamine was considered inappropriate. Denkler and Cohen ³⁶ describe the use of topical nitroglycerin for the treatment of dopamine extravasation into the dorsum of the left hand and the left ankle of a premature infant. A 1-inch strip of 2% topical nitroglycerin was applied to both sites approximately 2 to 3 hours after symptoms of extravasation were noticed. Within a few hours, symptoms at both sites resolved, and the areas of extravasation appeared normal. Wong et al ⁴⁰ reported successful use of 4 mm/kg of 2% nitroglycerin for treatment of dopamine extravasation in neonates, with no hemodynamic side effects noted. Sodium nitroprusside, on the other hand, was found to be ineffective despite its potent vasodilating properties. Supportive care measures with warm compresses, elevation of the affected limb, and wound care can also facilitate healing.^30,37,38

Vasopressin

Vasopressin is a peptide hormone released from the posterior pituitary gland in response to decreased intravascular volume, osmolarity, and/or pressure. In the setting of hemodynamic instability, low-dose exogenous vasopressin can increase systemic vascular resistance and decrease the requirements for catecholamines.

Depending on the indication, vasopressin can be administered via many different routes, including intravenously, intramuscularly, or subcutaneously. Vasopressin has a pH of 2.5 to 4.5 and is generally diluted to a concentration of 0.1 to 1 unit /mL when administered as an infusion. ¹³ Although there is no direct correlation between vasopressin concentration and extent of tissue damage with extravasation, 1 case of severe tissue necrosis has been reported. Kahn et al ⁴⁶ report a case of vasopressin infused at 0.04 units/min through a peripheral line in the setting of refractory septic shock. Progressive tissue damage continued to occur despite stopping the infusion and applying warm compresses as treatment. No other published studies of low-dose vasopressin extravasation have been reported. Although not commonly recommended, administration of low-dose vasopressin through a central line for septic shock would be an option to avoid this complication. ⁴⁶ Cases of cutaneous gangrene have been reported in a small number of patients who were receiving vasopressin 20 units/hour for the treatment of portal hypertension. It is important to note that the causative agent for cutaneous gangrene in 4 out of the 5 cases cannot be clearly linked to vasopressin extravasation and remains unclear. ⁴⁷

Mannitol

Mannitol is an osmotic diuretic that works directly at the proximal tubule and descending loop of Henle in the kidneys to prevent the reabsorption of free water and sodium. This type of diuresis is useful in situations where increased urinary excretion is necessary and to reduce elevated intracranial pressure secondary to head injuries. Mannitol solutions are hyperosmolar (1098 mOsm/L) ¹³ and can cause swelling and severe edema by drawing fluid into the extravasated tissue. The increased pressure from edema can lead to compartment syndrome characterized by reduced blood flow, tissue necrosis, and nerve damage.

In cases of diagnosed compartment syndrome, emergent fasciotomy is required to relieve fluid pressure. This procedure is often traumatic and potentially disfiguring.^48-51 For less severe cases of extravasation, the use of hyaluronidase and warm compresses has been reported. ⁵² Kumar and Sprung ⁵² report the extravasation of 20% mannitol in the dorsal right hand of a man undergoing general anesthesia for a procedure. The patient experienced significant swelling in his hand with delayed capillary filling. When treatment with warm compresses and elevation failed to provide relief, 150 units of hyaluronidase was injected subcutaneously in 0.5- to 1.0-mL increments to the periphery of the site. Complete resolution of the area occurred the following day, and no surgical intervention was required.

Parenteral Nutrition and Electrolytes

Hypertonic agents such as total parenteral nutrition (TPN),^5,53-56 dextrose >10%,^57,58 calcium solutions,^57,59-61 potassium solutions,^5,57,62,63 and sodium bicarbonate^5,57,59,62 exhibit the potential to cause tissue damage by shifting the equilibrium between intracellular and extracellular fluid. Intracellular fluid is forced out of cells and into the interstitial space, causing direct cell damage. In addition, increased fluid and pressure can lead to acute limb compartment syndrome with damage to the surrounding muscle and nerves. Inadvertent leakage of these agents has been reported to cause significant sequelae, especially in the neonatal population. Skin grafting, wound debridement, and limb amputation have all been reported as necessary treatment options.^53,57,64,65 Noninvasive therapies with topical nitroglycerin to prevent tissue ischemia and amorphous hydrogel to promote wound autolysis have been successfully used to treat TPN extravasation in neonates.^54,55 Wiegand and Brown ⁶⁶ report complete resolution with the use of hyaluronidase and cold compresses for the treatment of dextrose 5% solution extravasation.

Calcinosis cutis, a term used to describe a rare condition of calcium deposition in the skin, was first described in 1936 and has since been well described in the literature as a result of calcium solution extravasation.^56,67-77 The formation of amorphous masses or diffuse subcutaneous plaques may take days to weeks to develop, appearing as firm, white to yellow nodules on the skin. ⁶⁷ There is no standard treatment for calcinosis cutis. Supportive care with arm elevation and cold compresses has been recommended. ⁷⁴ Surgical removal of the calcium deposit may be necessary. ⁷⁰

Arginine

l-Arginine is a naturally occurring amino acid produced in the human body. It is widely available as a natural supplement. Arginine hydrochloride injection is available for use as a diagnostic agent, often used to test for growth hormone production in pediatric patients. It has also been studied for a variety of other indications, including metabolic alkalosis, genetic urea cycle disorders, and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Intravenous arginine has a pH of 5.6 and is hypertonic at 950 mOsm/L. ⁷⁸ Venous irritation is a known side effect associated with arginine infusion. Cases of arginine extravasation have been reported in pediatric patients ranging from 10 months to 9 years of age.^79-82 In 2 of these cases, arginine extravasated into the surrounding tissue and caused partial to full-thickness necrosis requiring skin grafts despite initial treatment with cold compresses and limb elevation.^80,81 In another case, conservative therapy with cold compresses and compressive dressings resulted in resolution of the wound without the need for skin grafting or debridement. ⁸²

Phenytoin

Phenytoin is one of the most widely used antiepileptic drugs available. Phenytoin sodium, the injectable form, is most commonly used to control status epilepticus in patients who are hospitalized or unable to tolerate any medication by mouth. Each 50 mg/mL vial of phenytoin solution contains approximately 40% propylene glycol and 10% alcohol adjusted to a pH of 12 with sodium bicarbonate. ¹³ Because of its poor solubility and tendency to precipitate, intravenous phenytoin should be administered using an in-line 0.22- to 5-µm filter at a maximum rate of 50 mg/min to avoid systemic toxicity. The proposed mechanism of tissue damage from extravasation involves all the aforementioned properties: vehicle composition, strongly alkaline pH, and precipitate-forming abilities.

Many cases of phenytoin extravasation have been reported.^83-89 Rao et al ⁸⁴ reported 3 cases of phenytoin extravasation with different interventions and varying degrees of severity. In the most severe case, a fasciotomy was performed after the patient experienced rapid swelling and discoloration of the hand from phenytoin extravasation. Despite aggressive surgical intervention, the patient eventually developed necrosis at the fingertips and distal forearm requiring amputation of the hand. In mild cases of phenytoin extravasation, elevation of the affected limb and close observation is recommended and reportedly successful. Risk factors for phenytoin extravasation include undiluted administration, small IV catheters, and rapid infusion greater than 25 mg/min. ⁸⁵

Hyaluronidase has been used for the treatment of extravasated phenytoin successfully. In 1 case report involving extravasation in a pediatric patient, repeated doses of subcutaneous hyaluronidase administered into sites surrounding the area resulted in decreased swelling and complete resolution. Other treatment options described include warm compresses and transdermal nitroglycerin patches.^83,86-89

Promethazine

Promethazine is a common drug used as an antiemetic, antihistamine, and sedative. Although promethazine is available in tablet, liquid, suppository, and injection forms, the intravenous route is the most popular route of administration primarily because of its rapid onset of action. Intravenous promethazine made headline news across the country in early 2000 when cases of intravenous promethazine extravasation caused severe tissue gangrene that required amputation. A 19-year-old patient was given IV promethazine in the emergency department for nausea. The drug extravasated during administration. The resulting necrosis was so severe that 3 fingers were eventually amputated. IV promethazine is highly irritating and acidic, with a pH of 4 to 5.5. ¹³ According to a safety report published by the Institute for Safe Medication Practices, 3 incidences of promethazine extravasation required amputation.^80,91

The significant morbidity of this error has led to widespread education and change in clinical practice. The preferred route of administration for parenteral promethazine is intramuscular. However, if intravenous promethazine is used, the maximum recommended concentration should be 25 mg/mL. Administration should be through large, patent veins, given slowly over 10 to 15 minutes and preferably diluted to enable slow administration. More drastic changes to clinical practice include removing promethazine from the formulary or prohibiting use of the IV route.^80,91

Propofol

Propofol is a common anesthetic used for general sedation and for sedating mechanically ventilated patients in the intensive care unit. Propofol seems innocuous, being isotonic and having neutral (pH of 7-8.5) chemical properties. ¹³ However, a handful of cases involving tissue damage and necrosis with propofol extravasation have been reported.^92-98 In the case of a patient receiving propofol for mechanical ventilation, a blister with underlying necrotic tissue developed at the site of infusion. Supportive therapy with limb elevation and wound dressings were applied with complete resolution. ⁹⁵ Another case of tissue necrosis associated with propofol extravasation was described in an infant during general anesthesia. Early signs of tissue necrosis in the right foot required wound debridement and skin grafting by plastic surgery. ⁹⁶ Supportive care with cold compresses was used by Huijbers et al ⁹⁷ for a patient when propofol extravasated into the back of the patient’s left hand during general anesthesia. The patient reported significant pain, but no soft-tissue damage was noted. The area completely resolved with no permanent sequelae.

Sodium Valproate

Valproic acid therapy is used to treat both seizures and mood disorders. Sodium valproate solution for injection (valproic acid) has a pH of 7.6. ¹³ Maintenance doses of sodium valproate should be administered at a rate of no more than 20 mg/min. However, in urgent situations, sodium valproate may be given as a rapid infusion at up to 6 mg/kg/min. Rapid administration of sodium valproate into a peripheral line is known to commonly cause pain and irritation. ⁹⁹ However, extravasation or infiltration of valproic acid into surrounding tissue has rarely been reported. Santivasi et al, ¹⁰⁰ in a case report, described a patient who developed large fluid-filled bullae after an infusion of 500 mg of valproic acid in 50 mL of dextrose through a peripheral line placed in his right hand. Edema at the site of extravasation progressed into the upper extremity, leading to compartment syndrome. The patient required emergent escharotomy to relieve tissue pressure. Although the exact mechanism of tissue damage is unknown, the authors note contributing factors to include local infusion accumulation, direct toxic effects, and possibly low tissue carnitine levels as a result of long-term valproic acid therapy. ¹⁰⁰

Sodium Thiopental

Sodium thiopental is a fast-acting barbiturate used for the induction of general anesthesia and is more commonly known to cause thrombophlebitis.^101,102 On the other hand, extravasation management is limited to the experience of 1 case report. Mao et al ¹⁰¹ reported the use of 2% lidocaine injected into the affected catheter and 15 g EMLA cream applied over the affected area for the treatment of suspected extravasation. The area completely resolved after 48 hours with no long-term sequelae. ¹⁰²