Use of Viable Cryopreserved Umbilical Tissue for Soft Tissue Defects in Patients With Gas Gangrene: A Case Series

Introduction. Gas gangrene is a rapidly progressive bacterial infection leading to necrosis that usually develops as a result of trauma or postoperative complications. This condition requires early diagnosis with immediate surgical intervention. With a poor prognosis, a high incidence of amputation, and comorbidities such as diabetes and peripheral vascular disease, patients with gas gangrene are put at further risk for surgical complications. Objective. This case series reports the clinical outcomes of using a commercially available viable cryopreserved umbilical tissue (vCUT) in the surgical management of 10 patients (9 males, 1 female) with acute lower extremity gas gangrene. Materials and Methods. All 10 patients had aggressive debridement and irrigation, followed by an intraoperative application of vCUT to cover the large, complex wounds with exposed bone, tendon, and soft tissue, which was fenestrated and sutured to the surrounding skin edges. Results. The average wound size following debridement was 45.9 cm² (range, 8 cm²–105 cm²). Average percent area reduction of the wounds at 4 weeks post-vCUT application was 68.4% (range, 49%–99.5%). The average length of hospital stay was 9 days (range, 2–16 days), and postdischarge patients were treated with negative pressure wound therapy and standard of care (nonadherent dressing, dry gauze, and mild compression) until wound closure was achieved (average, 3.3 months [range, 1.25–4.5 months]). With a 1-time application of vCUT, all patients reached complete wound closure with decreased time to closure, fewer complications, and a shorter duration of hospitalization as compared with traditional inpatient management of gas gangrene (incision and drainage with staged procedures). Conclusions. The positive clinical outcomes indicate that vCUT may be an effective aid as an intraoperative application to cover wounds following aggressive debridement in the presence of gas gangrene.

Gas gangrene typically occurs when a site of injury caused by trauma or surgery becomes infected; however, it also can occur without obvious injury.1Clostridium species, which cause gas gangrene, release toxins, leading to an accumulation of gas and rapid myonecro- sis with fatal deterioration of the whole body. Successful management requires urgent diagnosis and intervention in or- der to avoid tissue necrosis and amputa- tion. Surgical intervention, debridement, and excision of infected tissue are critical steps in the treatment of gas gangrene.

Patients with diabetes and periph- eral vascular disease (PAD) are further compromised. Such comorbidities are well-recognized causes of amputations; 82% of vascular-related lower extremity amputations in the United States are associated with diabetes.2 Patients with diabetes also have a 30-times greater lifetime risk of having a lower extremity amputation than patients without dia- betes.2 The 1-year post-lower extremity amputation mortality rate is reported to be between 10% and 50%, and the 5-year post-lower extremity amputation mortality rate is as high as 80%.3

Immediate incision and drainage (I&D) with aggressive debridement and irrigation is the standard management of acute gas gangrene, but this often results in large open wounds due to a lack of adequate surrounding soft tissue and skin required for surgical wound closure. Exposed bone, tendon, and soft tissue increase the risk of complications, including nonhealing wounds, sepsis, and amputation.4 Complex wounds are one of the most common precursors to lower extremity amputations and are 11 times more likely to result in higher- level amputations such as below-knee or above-knee amputations as compared with a fully granulated wound.5,6 Due to the severity of such complex wounds, rapid closure is critical to prevent higher-level amputations. Graft options for complex wounds are limited, as split- and full-thickness skin grafts and bilayer bovine collagen matrix (INTEGRA Bilayer Matrix Wound Dressing; Integra Life Sciences, Plainsboro, NJ) do not have the indication for direct application over exposed bone, muscle, or tendon or in the presence of infection. Muscle and vascular aps, rotational aps, or free aps can be utilized but have limitations (such as size, area of coverage, and location) in areas such as the foot and lower extremity and carry an increased risk of failure, especially in patients with diabetes with compromised vascularity.

More recently, commercial placental tissue grafts became available for wound treatment, including complex wounds. Placental tissue has anti-in ammatory, antioxidant, antimicrobial, and angiogenic properties that are bene cial for repair and regeneration of wounds.7-10Viable cryopreserved umbilical tissue (vCUT; Stravix; Osiris Therapeutics, Inc, Columbia, MD) is placental tissue composed of an outer amnion layer and inner stromal layer (Wharton’s Jelly). The vCUT retains a native collagen and hyaluronic acid-rich extracellular matrix, growth factors, and cytokines, as well as viable epithelial cells, broblasts, and mesenchymal stem cells present in fresh umbilical tissue. It is a soft, conform- ing, 1-mm- to 3-mm-thick durable graft that can be bene cial in covering large complex wounds following I&D of gas gangrene. This case series reports the clinical outcomes of vCUT use in the surgical management of 10 patients with acute lower extremity gas gangrene.

Study design and population

A single-center, retrospective chart review was conducted on 10 patients with diabetes and acute infections requiring immediate surgical intervention. Because the data collection was retrospective, Internal Review Board approval was not required for this study. Individual patient consents were obtained, and all patient data were de-identified. Inclusion of patients in this analysis was based on the presence of lower extremity gas gangrene diagnosed by radiography, ultrasound, or magnetic resonance imaging; a history of diabetes mellitus (DM); surgical intervention that resulted in large open defects with exposed bone, tendon, or soft tissue without adequate surrounding soft tissue or skin for surgical wound closure; and patients who were not candidates for autologous skin grafting or flaps. Of the patient population that met inclusion criteria (n = 10), 9 were male and 1 was female. The average age of the patient population was 59.8 years (range, 45–80 years). Five patients had partial 4th metatarsal amputations, 2 had 5th metatarsal amputations, 1 had a 2nd metatarsal amputation, and 2 had partial calcanectomies. The average wound size following debridement was 45.9 cm². Collective past medical history included DM, coronary artery disease (CAD), congestive heart failure (CHF), anemia, hypertension (HTN), PAD, gastroesophageal reflux disease, gout, hyperlipidemia, and hyponatremia.

Surgical technique

The patients were all taken to the operating room after having gas gangrene in the foot confirmed diagnostically. Patients were placed under monitored anesthesia care and positioned appropriately for optimal exposure. Immediate I&D was performed without tourniquet occlusion and with aggressive debridement of all infected, necrotic, and devascularized tissue and bone to the level of viable soft tissue and bone. Soft tissue and bone were cultured for growth of aerobic and anaerobic organisms. The surgical sites were irrigated with a motorized pulse lavage system. This was followed by a single application of fenestrated vCUT (3 cm x 6 cm) to the entire exposed wound surface, anchoring individual umbilical tissue pieces to each other as well as to the surrounding skin with either absorbable suture (4-0 or 5-0 plain gut) or skin staples. Fenestration of the tissue was performed with a #15 blade in small, alternating linear incisions. A nonadherent dressing (ADAPTIC TOUCH Non-Adhering Silicone Dressing; Acelity, San Antonio, TX) was placed over the tissue graft and secured in place with 3M Steri-Strips (3M, St Paul, MN). All patients received intravenous antibiotics during their hospital stay.

Analysis of clinical outcomes

Evaluation of clinical outcomes in vCUT-treated patients included the incidence of complete wound closure, the individual and mean percent area reduction (PAR) at 4 weeks, the mean time to wound closure, and adverse events, defined as any wound-related infection or amputation occurring during the vCUT treatment phase. Patients were also assessed at a 12-month follow-up in order to evaluate the durability of vCUT-assisted wound closures.

Surgical debridement and irrigation were followed by an application of vCUT. Negative pressure wound therapy (NPWT; V.A.C. Therapy; Acelity, San Antonio, TX) was used for a total of 5 to 7 days in 9 of the 10 patients. Wounds were not debrided during the postoperative period. Dressing changes consisted of nonadherent and dry dressings with mild compression. At 1 to 2 weeks, postoperative wounds appeared darkly discolored, which is the naturally occurring coloration of vCUT following application. Only 1 patient experienced a nongraft- related adverse event consisting of an amputation of the ipsilateral ischemic hallux, which the patient initially refused at the time of the vCUT surgery. All patients were admitted for inpatient care and discharged, on average, by postoperative day 9, followed by outpatient wound care with standard of care only (nonadherent dressing, gauze dressing, and mild compression). None of the patients were readmitted for complications.

Patient demographics and results of using surgically applied vCUT following debridement are summarized in the Table. Average wound PAR at 4 weeks was 68.4%. Average time to closure was 3.3 months (13.4 weeks). Scarring was minimal, natural pigmentation of the patient’s skin was restored, and function (range of motion and ambulation) was minimally limited. 

Case 1

A 65-year-old man with a history of uncontrolled type 2 DM, CAD, CHF, PAD, and HTN presented to the emergency department with a black 4th digit and infected dorsal aspect of the right foot. A radiograph revealed subcutaneous air with indistinct margins of the 4th digit. The patient was taken to the operating room for aggressive debridement.

All nonviable soft tissue and bone were debrided, and the 4th digit and 4th metatarsal head were amputated (Figure 1A). Liquefactive necrosis was noted. The wound measured 51 cm². The wound was irrigated with Pulsavac Plus (Zimmer, Inc, Warsaw, IN). The vCUT was applied and sutured with 4-0 absorbable sutures as well as the nonadherent dressing; NPWT was administered intermittently for 5 days at 125 mm Hg (Figure 1B). 

The dressing was changed 5 days after surgery, and the patient was discharged from the hospital. Weekly applications of the nonadherent dressing and dry sterile dressing were recommended, but due to documented noncompliance, the patient did not follow up from the date of discharge (postoperative day 7; Figure 1C) until postoperative day 35, with the same dressing still on his foot from time of discharge (dressing remained on for 28 days post discharge; Figure 1D). Despite this, the wound continued to granulate and heal without any further treatment (Figure 1E). After 1 application of vCUT, the wound granulated in 35 days and was epithelialized in 120 days (Figure 1F). The wound continued to remain closed without complications at 17 months follow-up (Figure 1G).

Case 2

A 76-year-old man with a history of type 2 DM, CAD, HTN, and PAD presented to the emergency department with an infected right heel (Figure 2A). Gas gangrene was diagnosed and the patient was taken to the operating room.

Immediate I&D and a partial right calcanectomy were performed after all of the necrotic and infected tissue was aggressively debrided. The initial wound area following debridement was 80 cm² (Figure 2B). Negative pressure wound therapy was applied intermittently for 4 days at 125 mm Hg during hospitalization (Figure 2C, 2D).

The patient was discharged from the hospital on day 12. At 4 weeks, the PAR was 52%, and time to wound closure was 12 weeks (Figure 2E-2G). 

Case 3

A 47-year-old man with a history of type 2 DM and an open wound of the dorsum of the left foot was seen in consultation after previously undergoing I&D for gas gangrene by another surgeon. Exposed bone and tendon with necrotic tissue were present 2 weeks after surgical debridement.

Revisional I&D with a 2nd metatarsal resection were performed with aggressive debridement and irrigation. The initial wound area post debridement was 105 cm² (Figure 3A, 3B). The vCUT was applied to the dorsal wound over the exposed bone and tendon, suturing the umbilical tissue pieces together and to the wound periphery (Figure 3C). Amputation of the ischemic hallux was recommended at the time of surgery; however, the patient refused and did not give consent. Negative pressure wound therapy was applied intermittently for 7 days at 125 mm Hg during hospitalization.

The patient was discharged on day 10. The PAR of the wound at 4 weeks was 61.2%, and time to wound closure was 17 weeks. The patient did undergo hallux amputation several weeks later; however, this complication was not related to the vCUT application (Figure 3D-3G).

Due to the high risk for complications with complex wounds, there is an ongoing demand for novel techniques and grafts that augment surgical management in compromised patients following open surgical debridement. Wound coverage options for the large defects created by I&D of gas gangrene are limited. The most common procedures include autologous skin grafting or flaps. However, high-risk patients with comorbidities often are not good candidates for autologous procedures due to the lack of healthy, well-perfused skin available for transfer, which correlates with the failure rate.¹¹

Recent clinical studies^12-14 reported durable closure of chronic wounds of various etiologies with viable cryopreserved membrane (vCPM; Grafix PRIME and CORE, Osiris Therapeutics, Inc). In an effectiveness review study using vCPM (PRIME), Suzuki et al¹³ showed clinical effectiveness in complex wounds characterized by exposed bone, tendon, muscle, or hardware. All 12 cases resulted in granulation over the exposed structures followed by complete wound reepithelialization without the adjunct use of NPWT, hyperbaric oxygen therapy, or surgical intervention. The mean 4-week PAR was 62.5%, and mean time to closure was 10 weeks with a mean graft use of 8.1 grafts.¹³ Frykberg et al¹⁴ reported positive clinical outcomes of vCPM in the management of complex diabetic foot ulcers with exposed tendon and/or bone, showing 96.3% of patients achieved 100% granulation and 59.3% of patients achieved complete wound closure by 16 weeks.

Viable cryopreserved umbilical tissue retains the properties and components of native placental tissue, including the 3-dimensional extracellular matrix, growth factors, living epithelial cells, fibroblasts, and mesenchymal stem cells.^7-10 It is a human tissue allograft regulated by the US Food and Drug Administration under Title 21 Code of Federal Regulations, Part 1271, Section 361, Human Cells, Tissues, and Cellular and Tissue-Based Products. It can be utilized as a wound cover, tissue wrap, or barrier for acute and chronic wounds of various etiologies at any location in the body. The vCUT is approximately 1-mm to 3-mm thick and suturable, making it better suited for many surgical procedures than thinner placental membranes.

These scientific and clinical data^7-10,12-14 suggest vCUT, as a thicker, more durable placental tissue, can be beneficial to augment the repair of open surgical sites in the foot. With the use of vCUT in 10 patients in this study, autologous flap procedures were avoided. This study is the first report of vCUT clinical outcomes in patients with diabetes and gas gangrene. All 10 wounds treated with only 1 application of vCUT achieved closure in an average of 13.4 weeks (range, 5–20 weeks) and prevented higher-level amputations.

Patients with comorbidities and postoperative open wounds, who are at risk for amputation, have to be hospitalized in order to control infection, maintain a stable environment, and reduce complications. In a 2010 database review at Boston Medical Center, Fincke et al¹⁵ reported on more than 60 000 patients with foot infections. Overall, 11 666 patients were hospitalized with gas gangrene. The median length of stay was 14 days, with a mean of 31.1 days.¹⁵ In the present 10-case series, patients were hospitalized for a median of 9.5 days, with a mean of 9 days (range, 2–16 days). Discharge was based on overall medical and surgical stability of the patient and discontinuation of inpatient intravenous antibiotics. Treating these surgical wounds immediately with aggressive debridement and application of vCUT may decrease the duration of hospital inpatient days, which the authors hypothesize could result in significant cost savings associated with earlier discharge.

Further randomized, prospective studies are warranted to confirm clinical and cost benefits of vCUT use in the surgical management of wounds.

The data presented in this case series demonstrate the potential clinical benefits of the surgical use of vCUT in patients with diabetes and gas gangrene. All 10 patients in this review achieved complete wound closure and avoided higher-level amputations. The use of vCUT following aggressive I&D may also reduce duration of hospitalization.

Affiliations: ¹Yale New Haven Northeast Medical Group Podiatry, Greenwich, CT; and ²Osiris Therapeutics, Inc, Columbia, MD

Correspondence: Dorothy H. Kurtz Phelan, DPM, Osiris Therapeutics, Inc, Department of Medical Affairs, 7015 Albert Einstein Drive, Columbia, MD 21046; dphelan@osiris.com

Disclosure: Dr. Kurtz Phelan is a paid employee of Osiris Therapeutics, Inc. Manuscript production support was provided by Osiris Therapeutics, Inc.