Pharmacology Review

Abstract

Extravasation or inadvertent infiltration of fluids into subcutaneous tissue from peripheral intravenous (IV) devices is a common adverse event in newborns. (1)(2) Although fluids occasionally extravasate from central venous lines, the complication is much more common from peripheral catheters, which are used widely in sick neonates. (3) This article focuses on extravasations from peripheral IV devices.Injury to the skin, even in a very immature neonate, results in an inflammatory response and heals by scar formation. (4) Although the scars from many of these injuries appear to improve with time, (5) tissue necrosis from extravasation injury could result in partial or complete skin loss, infection, and nerve and tendon damage, with the potential risk of permanent cosmetic and functional impairment. (6)(7)(8)The incidence of extravasations from Teflon® catheters has been reported to vary from 23% to 63%. (1) A recent survey of regional neonatal intensive care units in the United Kingdom recorded the prevalence of extravasation injury resulting in skin necrosis as 38 per 1,000 neonates, with 70% of these injuries occurring in infants of 26 weeks’ gestation or less. (2)The incidence of extravasation is related closely to the type of device used, insertion site, duration of therapy, infusate administered, patient activity, and gestational age. (1)(3)(9)(10) The fragility of the skin, particularly in the first 2 weeks after birth, and the lack of subcutaneous tissue in preterm neonates makes them uniquely susceptible to injury and skin loss.Extravasation may occur from the tip of the cannula or needle piercing the vessel wall. Alternatively, distal obstruction of the vein due to thrombosis or venoconstriction from irritation of the vessel wall may lead to increased back pressure and leakage from the entry point of the needle or cannula into the vein. (11)The terms extravasation and infiltration often are used interchangeably, as they are in this review. The Infusion Nurses Society defines extravasation as the inadvertent administration of a vesicant solution (one that causes blistering, usually antineoplastic drugs) into surrounding tissues and infiltration as the inadvertent administration of nonvesicant solution into surrounding tissues. (12) However, the distinction between vesicant and nonvesicant solutions is not clear in neonates, in whom parenteral alimentation fluids, antibiotics, calcium, potassium, and sodium bicarbonate solutions have the potential to cause necrosis and skin loss. (2)(13) The degree of cellular injury is determined by the volume of the infiltrating solution and physicochemical characteristics, such as pH, osmolarity, and degree of dissociability (pKa). Infiltration of vasopressors such as dopamine and epinephrine produces intense local vasoconstriction and tissue ischemia. (14)(15)(16)(17)(18)(19)The wide variation in the incidence of extravasation injuries in neonatal units may reflect practice styles or the vulnerability of certain populations. Measures to prevent extravasation include careful placement of peripheral venous cannulae in neonates, with appropriate taping to prevent movement yet ensure that swelling or erythema is not obscured. Frequent inspection of peripheral IV sites and regulation of delivery of IV fluids from continuous infusion pumps (usually limited to 1 hour at a time) may prevent the inadvertent infiltration of a large amount of fluid before detection. The infusion pump’s occlusion alarm should be set at the lowest possible limit. In a study of risk factors affecting infiltration of peripheral venous lines in infants, Phelps and Helms (9) showed that infusion device occlusion alarms did not detect infiltration reliably, registering increased pressure in only 19% of cases.Because the chemical characteristics of the intravenous fluid or medication could lead to intimal damage and, thus, to chemical phlebitis, obstruction, and extravasation, careful attention should be paid to the nature of the infusate. (20) Hyperosmolar fluids, acidic or alkaline solutions, or infusates that have irritant or vesicant properties should be administered through central venous lines if possible or diluted or neutralized appropriately.The use of heparin, either as a flush or added to continuous infusions to prolong peripheral catheter patency, remains unsettled. In an analysis of five randomized or quasi- randomized trials of heparin administered as a flush solution or as an additive to the total parenteral nutrition solution (versus placebo or no treatment), no statistically significant difference in the duration of catheter patency was found in two studies, but two other studies showed a statistically significant increase, and one study showed a statistically significant decrease in the duration of catheter patency in the heparin group. (21) In a more recent double-blind, placebo-controlled trial, the patency of peripheral intravenous catheters in neonates was prolonged by a mean of 7.4 hours when heparin was added at a concentration of 0.5 IU/mL infusion volume, but the incidence of infiltration/extravasation was the same in the heparin as in the placebo group (63.5% versus 64%). (10)Extravasation of IV fluids is marked initially by pain and swelling that subsequently progresses to blanching and signs of impaired perfusion. Objective staging of IV infiltrates (Table T1) has been used in some pediatric settings (22)(23) and is useful for quality improvement audits and for determining the degree of intervention required, but this cannot replace a detailed description of the clinical findings. (24) Fussiness, crying, and withdrawal of the limb when flushing the IV device are early warning signs, but these signs may be absent in infants who are sedated or critically ill. Blistering and discoloration of skin often presage at least partial skin loss, but visible skin changes do not always indicate the severity of underlying damage, which may evolve over several days. Persistent induration frequently progresses to a dry black eschar in 1 to 2 weeks, which then usually sloughs to reveal an ulcer. (8)Treatment is determined by the stage of extravasation, the nature of the infiltrating solution, and the availability of specific antidotes.In all cases of infiltration, the first step is to stop the intravenous infusion promptly and remove any constricting bands that may act as tourniquets (eg, armboard restraints). Elevation of the limb is recommended to reduce edema, but still may not prevent skin necrosis. (13) These measures probably are adequate for Stage I and II infiltrates, but there appears to be no consensus on further management, particularly for Stage III or IV lesions.A survey of regional neonatal units in the United Kingdom showed considerable heterogeneity in treatment, (2) which likely also is true in the United States. No randomized, controlled trials in humans have verified if certain interventions are more effective than others in reducing injury or scarring. Although there are some experimental data on animal models, the results may not be applicable to clinical situations in human neonates. Some institutions have established management protocols to guide therapy, but these are based on isolated case reports or case series. (22)(23) Treatment strategies vary from conservative to aggressive management of the acute injury, (6)(7)(25) with further variations on the management of the skin necrosis. (8)(13)(26) Comparison of the different strategies of treatment is confounded by heterogeneity in severity of the injuries, the nature of the infiltrating fluids, and factors such as gestational age and medical condition of the infants.The application of warm or cold compresses to areas of extravasation has not been studied systematically in neonates. Warm packs provide symptomatic relief of pain from phlebitis and may help to reabsorb infiltrating solutions by local vasodilatation. However, warm, moist compresses have been reported to cause maceration of the skin and subsequent necrosis in children. (13) Cold packs are presumed to decrease dissemination of the toxic substance into the tissues and to decrease cellular uptake of antineoplastic agents, but there are no data in neonates.For infants who develop blanching of the skin associated with absent capillary refill over the site of the lesion due to infiltration of acidic or hyperosmolar solutions, Chandavasu and associates (27) described a multiple puncture method to reduce the pressure and prevent skin necrosis. A sterile blood drawing stylet was used to make multiple perforations over the area of greatest swelling with strict aseptic technique. The infiltrating fluid was expressed out gently, and the area was dressed with saline soaks at room temperature to aid drainage. Improvement of the swelling was noted within a few hours, with complete recovery in 24 hours. The authors reported that since the method was instituted, no skin sloughs occurred over 1 year compared with two to three skin sloughs every week in previous years, even though 20% of the admissions to the NICU were very low-birthweight infants who required parenteral alimentation.In 1993, Gault described two techniques—liposuction and saline flushout—to remove or dilute the extravasated material to prevent injury in patients ranging in age from newborn to 70 years. (28) Liposuction was accomplished by inserting a blunt-ended liposuction cannula with side holes into the subcutaneous area after a small incision was made alongside the extravasation site under local or general anesthesia. The cannula was used to aspirate the extravasated material and subcutaneous fat.In the saline flushout technique, recommended for patients who have little subcutaneous tissue, such as preterm infants, the area of extravasation was infiltrated initially with hyaluronidase. Four small stab incisions were made around the periphery of the lesion, and a blunt-ended cannula with side holes was used to inject a large volume of saline (500 mL) in multiple small aliquots into the subcutaneous space, massaging the fluid toward the incisions to facilitate removal of the extravasated material. After flushout, a layer of paraffin-impregnated gauze dressing and povidone-iodine-soaked gauze was applied to the wound, and the limb was elevated for 24 hours. The stab incisions were allowed to heal spontaneously. Among patients who were treated within 24 hours of the extravasation, 88.5% showed no signs of soft tissue damage, and 11.4% exhibited minor skin blistering or delayed wound healing.The Gault techniques have been reported as being successful in neonates. (6)(25)(29) Davies and colleagues (29) described two preterm infants of 24 and 28 weeks’ gestation who were treated successfully with the saline flushout technique for infiltration of parenteral nutrition solution. Casanova and associates (6) treated 14 infants (age, 1 day to 6 months; mean weight, 2,490 g) within 3 to 12 hours of extravasation with a combination of liposuction and the saline flushout method. Six of the infants were preterm, and in 10 cases the adverse event occurred within 8 days of birth. The infiltrating solution contained dopamine in eight cases, a beta blocker in one case, and calcium or caffeine in the others. In the days following treatment, 11 cases improved, with no skin impairment, and the skin necrosis that developed in three infants healed spontaneously. Harris and coworkers (25) reported no skin or soft-tissue loss in a series of 56 newborns who had extravasation injuries that were treated with the saline flushout technique under local anesthesia. These reports provide no details of the severity of the extravasations, although the lesions probably were at least Stage III to warrant such invasive management.Animal models that have been developed recently and tested to standardize the extravasation injury appear to show that saline flushout is effective in reducing the area of necrosis, particularly if treatment is initiated within 1 hour of injury. (30)(31) Treatment with hyaluronidase is an integral part of the Gault saline flushout technique, but it is not clear if the technique would be as effective without the use of hyaluronidase.Hyaluronidase, a protein enzyme, enhances the distribution and reabsorption of extravasated fluids by breaking down hyaluronic acid in the ground substance of connective tissue, increasing tissue permeability, and reducing tissue destruction by decreasing the local concentration of noxious chemicals in the area of extravasation. Hyaluronidase for pharmaceutical use usually is derived from bovine testicular tissue extracts. Its manufacture in the United States was discontinued more than 3 years ago for uncertain reasons. The United States Food and Drug Administration recently approved an ovine form of hyaluronidase (FDA Talk Paper, May 6, 2004).Animal experiments and clinical reports have shown the effectiveness of hyaluronidase in reducing the degree of skin loss and ulceration due to infiltration of vesicant chemotherapeutic agents and radiographic contrast agents. (32)(33)(34)(35) Laurie and associates (32) demonstrated in a rabbit model that hyaluronidase was most effective in reducing the area of necrosis when used immediately after extravasation of a calcium chloride hyperalimentation solution containing 25% dextrose and doxorubicin; delays of more than 1 hour in treatment with hyaluronidase resulted in no statistically significant reduction of the area of necrosis. Heckler (34) reported on the successful use of clysis using a mixture of hyaluronidase and saline (150 U/1,000 mL saline) to decrease skin necrosis in an experimental rabbit model as well as in 148 patients who had extravasations of antineoplastic agents (primarily doxorubicin). All patients were treated within 1 hour of the acute exacerbation, using 12 to 38 mL of the saline/hyaluronidase solution. None of the patients suffered full-thickness skin loss, and none required debridement or skin grafting.Hyaluronidase has been used in neonates who experienced infiltrations of high-concentration dextrose, calcium, sodium bicarbonate-containing solutions, nafcillin, and other antibiotics (32)(35) Zenk and colleagues (35) showed that necrosis was avoided in two infants when hyaluronidase (15 U/1 mL of normal saline) was used within 1 hour of infiltration of nafcillin compared with severe tissue necrosis and skin sloughing in a 4-month-old infant who suffered extravasation of a less concentrated solution of nafcillin in a larger volume of fluid who did not receive hyaluronidase treatment.The dose of hyaluronidase used in neonates ranges from 15 U/1 mL (35) to 500 to 1,000 U used in conjunction with saline flushing techniques. (29) Although rare allergic reactions have been reported in adults, none have been reported in neonates. Hyaluronidase is not recommended for use in infected areas because of the risk of spreading a localized infection. Standard reference manuals state that hyaluronidase is not indicated for treatment of extravasations of vasoconstrictive agents, (36) but there have been reports of successful treatment of such injuries with a combination of hyaluronidase and saline irrigations. (6)(25)Dopamine, a catecholamine, whose effects are mediated through stimulation of dopaminergic, alpha-, and beta-adrenergic receptors, is used frequently in critically ill neonates to treat hypotension and shock syndromes. Stimulation of alpha-adrenergic receptors at high doses (>10 mcg/kg per minute) produces vasoconstriction. Although administration through central lines is preferred, dopamine frequently is administered through peripheral veins in concentrations of 2 to 20 mcg/kg per minute. Blanching of the skin over the surface of the superficial vein through which dopamine is being infused sometimes may appear as a long pale streak, but this usually is transient, and the blanching disappears when the infusion is discontinued or moved to another site. Extravasation of dopamine can cause severe tissue ischemia, necrosis, and gangrene due to intense local alpha-adrenergic receptor-mediated vasoconstriction. (14)(15)(16)(17)(18)(19) Peripheral tissue ischemia has been noted even with extravasations of low concentrations of dopamine (3 mcg/kg per minute). (17)(19)Phentolamine and nitroglycerin have been used to reverse the vasoconstrictive effects of catecholamine extravasations.Phentolamine, a potent alpha-adrenergic blocker, has been shown to reverse the ischemia caused by vasoactive drugs such as norepinephrine and dopamine in isolated case reports in humans. (17)(18) In a controlled trial of rats injected subcutaneously with the equivalent of a 5-hour infusion of dopamine at 15 mcg/kg per minute, investigators noted ectodermal blanching and pallor in the muscle fascia. (37) Subcutaneous injection with either 0.5 mg or 1 mg of phentolamine within 10 minutes of subcutaneous injection of dopamine appeared to decrease clinical erythema, induration, and blanching. Surprisingly, histologic examination also revealed increased erythema and hemorrhage in areas injected with dopamine compared with control areas injected with normal saline. Ischemic tissue necrosis was not established in this animal model, probably because the tissue samples were evaluated 2 to 8 hours after the injection, and demonstration of progression to necrosis may require several days.In the two case reports of neonates who had peripheral tissue ischemia due to dopamine extravasation, subcutaneous administration of phentolamine to the blanched area of infiltration resulted in immediate improvement of color and perfusion, with no untoward effects on the blood pressure and other vital signs. (17)(18) In both cases, phentolamine appeared to be effective, even when it was used more than 2 hours after the extravasation had occurred.The recommended dose of phentolamine varies from 0.01 mg/kg per dose (38) up to 5 mL of a 1 mg/mL solution, (36) depending on the size of the infiltrate. The use of repeated small doses, with close monitoring of blood pressure, probably is prudent in preterm infants because hypotension due to vasodilatation is a potential complication. The biologic half-life of phentolamine injected subcutaneously is less than 20 minutes.Nitroglycerin is a potent vasodilator that has been used for more than 100 years to treat angina pectoris in adults, but its mechanism of action still is debated. Vasodilatation is proposed to be by intracellular bioconversion to nitric oxide, which relaxes smooth muscle directly, or by the of the intracellular Alternatively, nitroglycerin may without the of nitric elevated acid which to of protein in produces vasodilatation by of intracellular calcium local vasodilatation by nitroglycerin has been used to reverse ischemia due to dopamine extravasation in a small of neonates. and colleagues described color and in two preterm neonates treated with local application of of nitroglycerin to the patient within 15 with complete of the areas within 2 hours. The other patient infant at 26 weeks’ required two of the 8 hours before all areas of ischemia A decrease in blood pressure and increased in the dopamine infusion were noted these but because the was to the nitroglycerin treatment, the of the to the hypotension is is well through skin, with concentrations related to the dose infants may be to and to the of the by 14 to days after because of through the immature The dose of 2 mg as mL in a was to be equivalent to no more than to 0.5 mcg/kg per administered of wound management in neonates who have or full-thickness skin loss is to or and if is recommended for most full-thickness and significant extravasation care the and vary from the wound to to with or or to saline or other dressing the area with every 8 hours. After 5 if the wound has healed but a of are to of a full-thickness eschar is applied to the eschar if to the wound and the eschar the wound is allowed to heal by and to with this from days to 3 should be that the risk of in who have and may be from the skin in very low-birthweight infants, In another trial of three different wound care using or sterile no significant difference was found in the of wound or in the (13) and associates the application of a every 8 hours with sterile saline gauze to the eschar and facilitate debridement and debridement and skin occasionally may be required in some infants these injuries to be a in newborns. is required to strategies for of these injuries and to develop management to wound and prevent when extravasations do include this under the it could well have been as a