Silver Toxicity With the Use of Silver-Impregnated Dressing and Wound Vacuum-Assisted Closure in an Immunocompromised Patient

Abstract

Silver-containing topical agents are used to help prevent infectious complications in wound therapy. Toxicity from topical silver agent exposure was initially reported in 1975 and was clinically characterized by granulocytopenia. Currently, the data regarding potential toxicity associated with silver-impregnated devices are limited. A 23-year-old patient receiving chemotherapy for acute lymphoblastic leukemia presented with necrotizing fasciitis of the abdominal wall and scrotum from a Crohn disease–related psoas-enteric fistula. Surgical debridement of the soft-tissue and abdominal musculature was performed to the peritoneum. Silver-containing foam sponges and wound vacuum-assisted closure were applied directly to the peritoneum 2 weeks after initial debridement. Subsequently, the patient developed leukopenia, and workup revealed the serum silver level was 4 times normal level. Silver-impregnated sponges were discontinued and silver-free sponges and wound vacuum-assisted closure therapy resumed, followed by leukopenia resolution. Silver toxicity associated with routine application of silver-impregnated sponges has not been previously reported.

Introduction

Silver used in the treatment of wounds was documented as early as the 17th century.¹ The development of targeted wound therapies has especially grown in the past half century, and since the 1960s, silver-containing topical agents and devices have been used for the prevention of infectious complications in wound therapy.² Silver toxicity with use of silver-impregnated devices is rare and has been characterized by the destruction of leukocytes.^3-5 Historically, silver toxicity has been attributed to silver sulfadiazine and has otherwise been associated with only one other silver-impregnated topical dressing. In this case report, we propose that elevated serum silver levels may result more easily from the use of silver-containing topical products and devices than previously believed and should be considered in the differential diagnosis of leukopenia. This report describes a critically ill patient who developed silver toxicity in the setting of necrotizing fasciitis treated with debridement and silver-containing foam sponges with negative pressure wound dressings.

Case Report

A 23-year-old man with a history of small and large bowel resection for Crohn disease at the age of 20 presented for reinduction chemotherapy for pre-B cell acute lymphoblastic leukemia. Three months into treatment, the patient developed severe abdominal pain and abdominal-wall tenderness with severely low white blood cell count (< 0.2/mm³ [< 200/μL]) and a low absolute neutrophil count of 120/mm³ (120/μL; Figure 1). On physical exam, the patient had a mild erythema of the anterior abdominal wall and severe pain out of proportion to physical findings. A computed tomography of the abdomen revealed a right psoas muscle–enteric fistula and an adjacent necrotizing soft tissue infection of the abdominal wall and scrotum.

Figure 1.

White blood cell and silver levels.

The patient underwent an emergent operation with subsequent debridement involving removal of the anterior abdominal wall musculature down to the level of the peritoneum. The enteric fistula was controlled with retroperitoneal Penrose drains. The patient’s wound was extensive, with an estimated wound surface area of approximately 50 cm² (Figure 2). Two weeks after the initial debridement, a wound vacuum-assisted closure (VAC) device with silver-impregnated sponges was applied directly to the peritoneum and was changed every 3 days. At this time, the patient was clinically improved, with a normal absolute neutrophil count. He was in remission of acute lymphoblastic leukemia, as confirmed by bone marrow aspirate. Two weeks after placement of the VAC with silver-impregnated sponges, his white blood cell count began to decline slowly. The persistent leukopenia prompted a serum silver level that was found to be 103 ng/mL, 7 times the normal level (0.0-14 ng/mL). After 28 days of VAC therapy with silver-impregnated negative pressure sponges, the silver-containing sponges were replaced with non–silver-containing sponges. The patient’s absolute neutrophil count soon returned to normal (3066/mm³ [3.066 × 10⁶/μL]), and 11 weeks after initial presentation, he underwent autografting to the abdominal wound. The wound continued to be dressed with a non–silver-impregnated sponge and wound VAC, and it healed progressively in the setting of the resolved leukopenia (Figure 3). The wound that originated from necrotizing fasciitis of the abdomen and scrotum had near complete healing 3 months after initial presentation (Figure 4).

Figure 2.

Abdominal wound post debridement.

Figure 3.

Abdominal wound with non–silver-impregnated sponge dressing.

Figure 4.

Abdominal wound after autografting.

Discussion

Silver was recognized as a customary treatment for ulcers and burn wounds as early as the 17th century and was considered a useful agent in the treatment of excessive granulation tissue in the 18th century.¹ While the mechanism of bactericidal properties of silver was poorly understood throughout that time, the development of the study of microbiology in the 20th century has led to improved comprehension of the mechanisms by which silver agents decrease wound infections.⁶ In 1973, work completed by Thompson indicated that silver ions were responsible for the antimicrobial effects of silver.⁷ Fox and Modak investigated the mechanism of action of silver sulfadiazine in 1974 and hypothesized that as silver ions were released into a wound, the ions caused cell membrane damage and eventual cell death.⁸ Their work was later supported by studies that confirmed silver ions bind to the cell wall components of bacteria, leading to disruption and eventual cell death, and the antimicrobial properties of silver have been found to be effective in eliminating several species of organisms, including bacteria, yeast, and mold.^9-11 The antimicrobial activity of silver works directly in the wound and is thought to promote healing by decreasing excessive neutrophil response and matrix metalloproteinase activity.¹² As the science of nanoparticle research has developed, our ability to comprehend the mechanism of action of silver on bacteria has become more precise, and there is evidence that antimicrobial effects of silver are achieved by both its ionic action and the nontoxic elementary silver nanoparticle.^6,13

Topical silver agents became increasingly common in wound therapy after Moyer reported using silver nitrate to treat burn wounds in the 1960s.¹⁴ Subsequently, topical silver sulfadiazine was added to the armamentarium of topical antibacterial agents and has essentially become the most commonly used agent.^5,15 Because of success in burns, the antimicrobial properties of silver have been extrapolated and employed in the development of a variety of medical devices for other wound applications, although several reports found no significant differences in infection rates.^2,16 For example, silver-containing polymers were developed for use in central venous catheters, urinary catheters, ventriculoperitoneal shunts, orthopedic prosthetics, and many other long-term implantable devices.^13,17,18 The true efficacy of silver-impregnated dressings remains elusive, and further investigation into antimicrobial properties in silver dressings, as well as silver-impregnated devices, is ongoing.¹⁹ Nevertheless, there has been an increase in the development of silver-containing dressings for the management of both chronic and acute wounds.²⁰

The use of topical negative pressure therapy for wound care has become widespread since 1997, when published work demonstrated that VAC assisted in completion of wound closure and enhanced formation of granulation tissue in the wound bed.²¹ The development of negative pressure wound therapy has continued to expand to optimize patient care, and in 2008 a silver-impregnated sponge used in conjunction with the VAC device (V.A.C.^® GranuFoam^™ Kinetic Concepts, Inc. [KCI], San Antonio, TX, USA) was introduced into clinical practice. The silver-containing sponge dressing was engineered for use with negative pressure dressings as a barrier against bacterial penetration, the possible reduction of bacterial infection, and the promotion of wound healing.²² Negative pressure wound therapy supports wound healing by decreasing the bioburden and increasing wound closure rates.^23,24 The use of wound vacuum devices has been evaluated in the trauma literature, and negative pressure therapy has been found to promote the formation of granulation tissue in addition to decreasing wound closure time.²⁵ Animal studies performed by the manufacturer KCI^® have compared negative pressure therapy using silver-impregnated sponges and nonimpregnated sponges.²⁶ While the colony counts detected in culture were reduced in the porcine model with the silver-impregnated sponge, no differences were observed in the average wound volume closure rates.²⁶

The effects of the use of silver dressings, however, truly have not been well defined. In 2010, a Cochrane Review did not identify an association between the use of topical silver dressings and either promotion of wound healing or wound infection prophylaxis.²⁷ Within a decade of the widespread use of topical silver wound treatments, leukopenia was observed in patients with burn wounds treated with silver agents.²⁸ In addition to medical exposure, there are several acute and chronic routes of exposure to silver, including ingestion, inhalation, and dermal absorption.²⁹ While all these toxicities are exceptionally rare, the range of toxic effects can include symptoms of corrosive damage to mucosal tissues, such as abdominal pain, vomiting, and diarrhea, and topical irritation to absorptive surfaces, which can occur through chronic occupational exposure.³⁰ One of the most well-known adverse effects of silver toxicity is argyria, a permanent blue-gray discoloration of skin. Thus far a single case report has been published that describes a case of argyria occurring in a patient with 30% burns treated with a silver-coated wound dressing.³¹

Our patient’s leukopenia was attributed to the elevated silver levels resulting from the use of the silver-impregnated sponge. Initially it was thought that the patient might have a transient leukopenia from underlying sepsis and malignancy. When the patient was noted to have a recurrent leukopenia, he was clinically well, and his acute lymphoblastic leukemia was in remission, as confirmed on bone marrow aspiration. The suspicion of silver toxicity was reinforced after documenting the resolution of the patient’s leukopenia shortly after removal of the silver-impregnated sponge.

While previous reports that have identified silver toxicity have been associated with larger wound surfaces as a percentage of total body surface area, this patient may have been at increased risk of silver toxicity due to direct application of the wound vacuum to a large surface area involving the peritoneum—a tissue membrane that has a high absorptive capacity.^5,32 Interestingly, we noted that once the silver-impregnated dressing was removed, the leukopenia abated despite continued increase in the patient’s serum silver level, suggesting that there may be an association with silver that is amplified by the direct application to a wound surface.

We report a case of silver toxicity in the setting of treating large-surface-area wound of the abdomen and peritoneum with VAC and silver-impregnated sponge. Silver toxicity should be considered in the setting of leukopenia in patients receiving therapy with silver-impregnated devices. To our knowledge, there are no reports in the literature that study the adverse effects of silver-impregnated sponges in humans. Further study of the benefits and risks of silver-containing devices needs to be pursued.