Use of Placental Connective Tissue Matrix to Heal High-Risk Below Knee Amputations

The healing of residual limb wounds is necessary to prevent further limb loss and improve quality of life. For patients with diabetes and severe peripheral vascular disease (PVD) with tissue loss, these authors demonstrate in a case series how a placental connective tissue matrix can be used to heal wounds that failed standard postoperative wound care.

Each year, approximately 300,000 below-knee amputations (BKA) are performed in the United States, with the majority in patients with uncontrolled diabetes or peripheral vascular disease (PVD).¹ As the prevalence of these comorbidities has increased, so have the rate of BKA and subsequent postoperative complications. Diabetes and PVD are comorbidities for BKA but are also associated with a higher risk of postoperative infection and poor wound healing. Although patients who undergo a BKA, compared to above the knee amputations (AKA), display greater rates of postoperative infection and need for revision surgeries, the BKA offers more favorable postoperative ambulatory function and mortality.²
    
A study by Sanders and Fatone demonstrates that an appropriately early time to prosthetic fitting offers restoration of a more natural gait pattern, long-term mobility and quality of life.³ Vogel and colleagues examined the association between amputation level and postoperative return to activity, reporting that patients with AKA demonstrated a slower return to activities of daily living.⁴ As such, proactive attempts are made to preserve the knee when considering amputation intervention, especially in patients who are at a higher risk for subsequent revision to improve quality of life and mobility for the patient.⁵
    
In order for the BKA wound to heal there must be adequate blood flow to distal skin flaps. Many case reports suggest that 15% of patients receiving of BKAs are converted to AKAs.⁶ This conversion rate is as high as 35% in high-risk groups, such as those with diabetes or peripheral vascular disease, who may display decreased blood flow to the region.⁷
    
Hasanadka and colleagues used the National Surgical Quality Improvement Program database to examine postoperative complications in patients who underwent lower extremity amputation.⁸ They noted that on average 5.1% of patients develop superficial site infections, 2.9% develop deep incision infections, and 1.7% of wounds dehisce. With these complex wounds it is difficult to cite an expected time to heal since the patients have significant comorbidities and stump complications. In addition, because there is no exact standard of care of the postoperative BKA patients requiring wound assessment and care, each institution has a different modality of treatment.
    
Many postoperative adjunctive treatments, such as negative pressure wound therapy (NPWT) and hyperbaric oxygen therapy (HBOT), have been used for BKA and AKA stump preservation with various reported efficacies.^9,10 Additionally, connective tissue derivatives have been used for decades as an adjunct to wound healing. Their suggested non-immunogenic, antimicrobial, and anti-inflammatory properties have inspired the development of several matrices that take advantage of these therapeutic properties for in vivo application.¹¹
    
Placental connective tissue matrix products have been successfully utilized to augment wound healing in certain high-risk populations, such as those with foot and ankle wounds, enterocutaneous fistulas, and burn injuries.^12–15 This case series looks at the use of a placental connective tissue matrix (PCTM) to heal complicated BKA wounds, with a focus on healing complex wounds in addition to standard of post-operative care for this small sample size.

Case Review

In this case review, 4 patients were identified and a retrospective chart review was performed to gather demographics, medical history, and surgical summaries. Each of these four patients had weekly follow-up in a vascular wound clinic that was overseen by the operative surgeon and nurse practitioner, and these visits were also reviewed via chart. These four patients were assessed for number of applications of PCTM, wound size, time of healing, and number of wound clinic visits.  

These patients each underwent BKA to treat complications of peripheral vascular disease, such as non-healing ulcers, local tissue infections, or gangrene. The same board-certified vascular surgeon performed each BKA in this study during a six-month period in 2019. The main outcomes assessed in this study included wound healing time and comorbidities of patients with high risk BKA.

The mean number of applications of PCTM was 4 (range 1–8) (see images). The same brand PCTM, Grafix (Osiris Therapeutics), was used in all patients. Additionally, traditional adjunctive therapies such as wet to dry dressings, chloropicrin, and Santyl (Smith and Nephew) were also used along with weekly debridement to assist with healing.

Demographics were also assessed, and the overall mean age of the cohort was 59 years (range 47–69 years). Cardiovascular disease was present in 50% (2/4), hypertension was present in 75% (3/4), and end stage renal disease was present in 50% (2/4) of the patients. History of failed prior lower extremity revascularization was present in 100% (4/4) of the patients along with tissue loss and or gangrene.

What You Should Know About Placental Connective Tissue Matrix

There is a high prevalence of comorbidities in patients who undergo BKA, which makes these patients higher surgical risks. These comorbidities play an important role in the pathophysiology that leads to a BKA, as well as increase the risk of postoperative complications after a BKA, such as chronic non-healing wounds, infection, or osteomyelitis. The majority of patients undergo BKA as a sequela of poorly managed diabetes or peripheral vascular disease, which contributes to poor baseline tissue vascular supply and wound healing potential.¹⁶ Novel techniques and adjuncts in postoperative management have been developed to further reduce the risk of complications in this high-risk patient population.

Several studies report post-BKA surgical site infection rates of 15–70%, with up to 30% of patients requiring operative revision.^6,17 However, patients in this series with BKA who received PCTM had significantly lower rates of post-operative infection, and decreased rates of operative revision. Additionally, the patients reported decreased pain with the use of PCTM. The lower rates of postoperative infection and revision surgery observed in the PCTM group are thought to be attributable to the proangiogenic and antimicrobial properties of the PCTM.¹⁸

The wound healing potential observed in the PCTM group is further substantiated by shorter wound healing times, and in turn we hope there will be a shorter time to prosthesis. This suggests that the PCTM adjust used in this study may reduce procedural morbidity while restoring early return to independent living (see Figures 1 and 2).

These properties of the PCTM may also play a factor in reducing the need for more aggressive operative management, such as surgical revision or conversion of a BKA to an AKA. Despite the higher rates of infection and operative failure seen with BKA in comparison to AKA, the lower mortality and ambulatory restrictions associated with BKA offer greater rehabilitative potential and more favorable outcomes.^19,20 In this small series, all wounds were able to be healed with PCTM and zero of the sample had conversion to AKA at time of this report which this small case study suggests that a post-procedural placental adjunct to treat postoperative wounds may improve the prognosis and recovery of this already compromised population.

One of the unique characteristics of these BKA wounds that healed was that these patients were followed weekly in a wound clinic. Warriner (2012) showed that diabetic foot ulcers healed more rapidly with weekly wound care.²¹ In addition to the PCTM promoting granulation tissue in the diabetic stump wounds, weekly assessments and debridement may have also played a role.

Strengths to this study included that this small cohort showed an improvement in the wound care of BKA patients with extensive comorbidities. A major limitation of this case series is its design as a single-center, single-investigator series with a small number of participants. Further large, randomized, prospective studies are needed to confirm the clinical applicability of a PCTM adjunct for high-risk populations that undergo BKA, specifically focusing on the conversion to a higher level of amputation in high-risk patients undergoing BKA.

This retrospective review was submitted to the University of Maryland Baltimore Institutional Review Board. Data collection and analysis was reviewed and secured and no confidential information was assessed.

Conclusions

This case series demonstrates favorable outcomes for patients who have had delayed postoperative wound healing of the BKA stump but have healed by using PCTM, specifically higher risk surgical patients with aforementioned comorbidities. Wound complications in BKA are common and often mandate the need for revision surgeries in a patient population with pre-existing comorbidities and greater operative risk. This case series in patients with severe PVD and diabetes with tissue loss shows PCTM can be used to heal the wound who had failed standard postoperative wound care. While further studies should be performed, providers should consider utilizing PCTM when a patient has failed conservative therapy following a BKA.

Eleanor Dunlap, ACNP-BC, is affiliated with the University of Maryland Medical Center.

Suzanna Fitzpatrick, DNP, ACNP-BC, FNP-BC, is affiliated with the University of Maryland Medical Center.

Megan Carroll, FNP-BC, is affiliated with the US Department of Veterans Affairs
VA Medical Center in Baltimore.

Khanjan Nagarsheth, MD, MBA, RPVI, is affiliated with the University of Maryland Medical Center.

1. Goodney PP, Beck AW, Nagle J, Welch HG, Zwolak RM. National trends in lower extremity bypass surgery, endovascular interventions, and major amputations. J Vasc Surg. 2009;50(1):54–60. doi:10.1016/j.jvs.2009.01.035

2. Moyer HR, Minter J. Salvage of an infected below-knee amputation with chlorhexidine and bi-layer dermal matrix: a case report. Surg Infect Case Reports. 2016;1(1):47–51. doi:10.1089/crsi.2016.0007

3. Sanders JE, Fatone S. Residual limb volume change: Systematic review of measurement and management. J Rehabil Res Dev. 2011; 48(8):949–86. doi:10.1682/JRRD.2010.09.0189

4. Vogel TR, Petroski GF, Kruse RL. Impact of amputation level and comorbidities on functional status of nursing home residents after lower extremity amputation. J Vasc Surg. 2014; 59(5):1323–30. doi:10.1016/j.jvs.2013.11.076

5. Schofield CJ, Libby G, Brennan GM, Macalpine RR, Morris AD, Leese GP. Mortality and hospitalization in patients after amputation: A comparison between patients with and without diabetes. Diabetes Care. 2006;29(10): 2252–2256. doi:10.2337/dc06-0926

6. Rosen N, Gigi R, Haim A, Salai M, Chechik O. Mortality and reoperations following lower limb amputations. Isr Med Assoc J. 2014; 16(2):83–7.

7. Columbo JA, Nolan BW, Stucke RS, et al. Below-knee amputation failure and poor functional outcomes are higher than predicted in contemporary practice. Vasc Endovascular Surg. 2016;50(8):554–558. doi:10.1177/1538574416682159

8.  Hasanadka R, McLafferty RB, Morre CJ, Hood DB, Ramsey DE, Hodgson KJ. Predictors of wound complications following major amputations for critical limb ischemia. J Vasc Surg. 2011;54(5):1374–1382. Doi:10.1016/j.jvs.2011.04.048

9. Sumpio B, Thakor P, Mahler D, Blume P. Negative pressure wound therapy as postoperative dressing in below knee amputation stump closure of patients with chronic venous insufficiency. Wounds. 2011; 23(10):301–8.

10. Columbo JA, Ptak JA, Buckey JC, Walsh DB. Hyperbaric oxygen for patients with above-knee amputations, persistent ischemia, and nonreconstructable vascular disease. J Vasc Surg. 2016;63(4):1082–4. doi:10.1016/j.jvs.2015.03.067.

11. Lullove E. A Flowable placental tissue matrix allograft in lower extremity injuries: a pilot study. Cureus. 2015;7(6):e275. doi:10.7759/cureus.275.

12. Haugh AM, Witt JG, Hauch A, et al. Amnion membrane in diabetic foot wounds: A meta-analysis. Plast Reconstr Surg - Glob Open. 2017;5(4):e1302. doi:10.1097/GOX.0000000000001302

13. Nichols F, Overly A. Case report novel approach for enterocutaneous fistula treatment with the use of viable cryopreserved placental membrane. Case Rep Surg. 2016. doi:10.1155/2016/8797691

14. Werber B, Martin E. A prospective study of 20 foot and ankle wounds treated with cryopreserved amniotic membrane and fluid allograft. J Foot Ankle Surg. 2013; 52(5):615-21. doi:10.1053/j.jfas.2013.03.024

15. Eskandarlou M, Azimi M, Rabiee S, Seif Rabiee MA, Rabiee MAS. The healing effect of amniotic membrane in burn patients. World J Plast Surg. 2016; 5(1):39–44.

16. Lavery LA, Hunt NA, Ndip A, Lavery DC, Van Houtum W, Boulton AJM. Impact of chronic kidney disease on survival after amputation in individuals with diabetes. Diabetes Care. 2010;33(11):2365-9. doi:10.2337/dc10-1213

17. Wong KL, Nather A, Liang S, Chang Z, Wong TTC, Lim CT. Clinical outcomes of below knee amputations in diabetic foot patients. Ann Acad Med Singapore. 2013;42(8):388-94. doi:24045374

18. Gibbons GW. Grafix^® , a cryopreserved placental membrane, for the treatment of chronic/stalled wounds. Adv Wound Care. 2015; 4(9):534–544. doi:10.1089/wound.2015.0647

19. O’Brien PJ, Cox MW, Shortell CK, Scarborough JE. Risk factors for early failure of surgical amputations: An analysis of 8,878 isolated lower extremity amputation procedures. J Am Coll Surg. 2013; 216(4):836–44. doi:10.1016/j.jamcollsurg.2012.12.041

20. Wu JT, Wong M, Lo ZJ, et al. A Series of 210 peripheral arterial disease below-knee amputations and predictors for subsequent above-knee amputations. Ann Vasc Dis. 2017; 10(3):217–222. doi:10.3400/avd.oa.17-00046.

21. Warriner, RA. More frequent visits to wound care clinics result in faster times to close diabetic foot and venous legs ulcers. Adv Skin Wound Care. 2012; 25(11):494–501. DOI: 10.1097/01.ASW.0000422629.03053.06