Challenging Cases: Neonatal Skin and Soft Tissue Necrosis Leading to Amputation

This month’s column begins with a 2-day-old ex 33-week gestational age female who was transferred to Cohen Children’s Medical Center of New York because of concerns about left forearm/hand ischemia due to a dusky color at birth. The patient had edema, erythematous scalding-like lesions, and weakness of the left upper extremity at birth. Radiographs revealed normal bones. The pregnancy was remarkable for maternal active herpetic lesions; therefore, cesarean section was performed. The mother had contracted severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection late in her second trimester. The result of the real time reverse transcription polymerase chain reaction (rRT-PCR) was positive. Physical examination at our facility revealed large necrotic areas over the left forearm and hand, surrounding erythema, edema, contractures of distal phalanges, and lack of a pulse at the wrist (Figure 1).

Initial evaluation revealed thrombocytosis and elevation in coagulation parameters. The patient’s D-dimer levels were very high (1270 ng/mL), antithrombin was low, partial thromboplastin time was elevated, and fibrinogen was normal. The patient was started on continuous heparin infusion and transitioned to subcutaneous enoxaparin twice a day as per vascular surgery. Plastic surgery and orthopedics services followed the case. Further coagulation evaluation revealed normal factors, including factor V Leiden, protein C, protein S, prothrombin time, anticardiolipin antibody, ß2 glycoprotein, negative work-up for neonatal lupus and pro-thrombotic inflammatory indices, such as interleukin-8 (IL-8), and normal clotting times. Her IL-10 level was elevated.

Doppler ultrasound confirmed a lack of radial arterial signal past the forearm and no evidence of deep venous thrombosis. Magnetic resonance imaging revealed no flow to the patient’s left hand, possibly indicating an arterial thrombus. Both radial and ulnar arteries were not visualized past the wrist. Etiology was not clear, but potentially could have originated from maternal placenta as pathology revealed a venous thrombus within 3 cm of insertion. Placental venous thrombi can embolize to the umbilical vein, travel to the inferior vena cava, and enter the heart, where they can be shunted to the aorta. Given the maternal COVID-19–positive status and current understanding of COVID-19 as a hypercoagulability disease, we could not exclude a COVID-19–related thromboembolic event causing patient hand ischemia, especially because extensive work-up of potential etiologies was negative. The infant had SARS-CoV-2 antibodies, likely from transplacental maternal transmission, and negative rRT-PCR for active COVID-19. Compartment syndrome and arterial malformation also were considered, but both were ruled out.

I was consulted about wound and skin management. At that time, the orthopedics department had planned an amputation at the elbow level. We were hoping to salvage some tissue and possibly minimize the amputated length. With that aim, we immediately added nitroglycerin 2% ointment twice a day to all affected areas, alternating with concentrated surfactant gel (CSG) twice a day. The left upper extremity showed evidence of significant ischemic compromise; the fingers, hand, and lower wrist area continued to show evidence of necrosis, evolving contractures of the fingers, and no grasp reflex. Ischemic areas on the volar forearm and radial distribution had diminished (Figure 2). Necrotic eschars started to demarginalize from the healthy tissue. We added an enzymatic debrider (Collagenase Santyl, Smith & Nephew, Fort Worth, TX) to all necrotic areas over the patient’s forearm to soften and gently debride the dead tissue, with the hope of saving as much tissue as possible with the nitroglycerin/surfactant combination. Methylene blue/gentian violet infused foam dressing was chosen as an outer dressing to complement the debridement (Figure 3) and an outer Covidien Kerlix gauze (Medtronic, Dublin, Ireland).

Within 3 to 4 days of the addition of the enzymatic debrider, forearm slough had softened, facilitating the first debridement (Figure 4). This was followed by 2 more debridements on the following days (Figure 5). We were happy to see healthy tissue underneath the slough, despite pretty deep necrosis of epidermal and dermal layers. There was a clear demarcation between lower forearm tissues and liquefied necrosis at and below the wrist. The decision for amputation of the hand and lower forearm was made, which the patient tolerated without complications. Most of the forearm was saved.

This rare case of neonatal upper extremity amputation due to arterial thrombus raises many unanswered questions as well as highlights a strategy that I have used in multiple cases of upper and  lower extremity ischemia due to venous/arterial thrombosis and tissue necrosis.

The definitive etiology of this limb ischemia remains unknown. It is speculated that this could be a COVID-19–related ischemic injury in the context of transplacental thrombi translocation. There are only 2 case reports of vertical transmission of COVID-19 in the literature.¹ In both cases SARS-CoV-2 RNA was found in placental tissue, syncytiotrophoblast, signifying the presence of the virus on the fetal side. The virus was not isolated from the fetal placental tissue in the current case; therefore, I do not believe that the infant had intrauterine COVID-19 disease. Placental pathologies in COVID-19–positive mothers have encompassed the following findings: maternal vascular malperfusion, particularly decidual arteriopathy, intervillous thrombi, avascular villi, fibrin deposition in fetal vessels, chorioamnionitis, and large chorangiomas.² Researchers believe that frequent intervillous thrombi in patients with COVID-19 represent placental formation and deposition of thrombi in response to the virus.² Given a thorough work-up and negative results for other etiologies, I believe that the cause of this infant’s cutaneous and soft tissue necrosis was COVID-19–related transplacental thromboembolism, leading to upper extremity arterial thrombosis.

Neonatal limb ischemia is a relatively rare event, yet significant morbidity and loss of function risks command improvements in management. Skin and soft tissue loss present significant challenges. Events causing ischemia are divided into intrauterine and postnatal.^3,4 Intrauterine ischemia is further classified into compression ischemia and thromboembolic phenomena. Neonates in general have a hypofibrinolytic state and an immature anticoagulation system.^3,4 Certain maternal factors, such as diabetes, sepsis, or heart disease, may exacerbate this neonatal hypofibrinolytic state. Maternal-origin placental emboli may pass via the fetal foramen ovale and lodge in the fetal upper limb, causing ischemia, necrosis, and sometimes the need for amputation.^3,4 Treatment goals are to preserve salvageable tissue, minimize further damage by anticoagulation, and minimize end-organ loss or amputation.

Tissue-saving treatments can be supportive or interventional. Interventional therapies include thrombolysis using a tissue plasminogen activator or surgical thrombectomy if a vital organ is compromised and a large, accessible clot is identified.^3,4 The supportive treatments I use include intravenous hydration, anticoagulation and topical vasodilators, tissue-salvage topical products, and wound-debriding/tissue-stimulating products. Results vary depending on the length of time between the initial vascular event and presentation; nonviable areas will often declare themselves over time with fixed tissue changes and necrosis.

The use of nitroglycerin 2% ointment has been successful in improving ischemia-related upper and lower limb vasospasm due to central line placement, nonocclusive thrombi, and severe extravasations.^5–7 Topical application leads to local area vessel vasodilation, improvement in perfusion, and improved tissue viability. In my experience, applying nitroglycerin ointment reduces tissue and skin loss. It is applied 2 to 3 times a day, with a thin layer to all affected areas, and covered loosely with an outer dressing. Blood pressure must be monitored frequently because nitroglycerin is a systemic vasodilator. However, I have very rarely seen blood pressure drop in general, and never low enough to the point where discontinuation of the nitroglycerin would be warranted. 

I alternate nitroglycerin ointment with concentrated surfactant burn and wound dressing (PluroGel Burn and Wound, Medline Industries Inc., Mundelein, IL). CSG is a biocompatible, noncytotoxic, non-anionic, synthetic poloxamer 188-based surfactant biomaterial composed of a central hydrophobic chain of polyoxypropylene and 2 hydrophilic chains of poloxyethylene. In an aqueous solution, surfactant molecules form micelle and eventually the micelle matrix. Certain areas of injury may undergo evolving changes and, if caught early enough, cells can be salvaged. The amphiphilic properties of poloxamers allow them to insert into the cell membrane deficient of the lipid’s bilayer. The surfactant molecules seal the damage, allowing injured cells to repair and produce further lipid molecules.^8–10 Once sealed by the exogenous lipids, the cell is able to “squeeze out” the CSG molecules and stay healthy. In addition to debridement, studies have demonstrated decreased biofilm formation on wounds with CSG as well as effective biofilm disruption and bacterial infection treatment. Percival et al demonstrated effective biofilm prevention by CSG by immobilization of planktonic bacteria.⁸ Yang demonstrated reduction in bacterial biofilm after 3 days of application and wiping of the gel.¹¹ Bioflim disruption can be challenging because extrapolymeric substances protect bacteria from antimicrobial agents’ penetration. CSG can penetrate the biofilm capsule and disperse biofilm.^12,13 A decrease in inflammation has been reported with CSG use via biofilm, proteases, bradykinin, and pro-inflammatory cytokine removal.⁸ 

I usually continue this combination for 3 to 4 days, which allows true, unsalvageable necrotic areas to delineate themselves. The dead tissue darkens and dries, and phalangeal tips get reabsorbed or shrivel up. Salvageable tissue will either be debrided or, if necessary, further broken down with an enzymatic debrider to augment sharp or mechanical debridement as shown in this case.

I often enhance this process by an antimicrobial, absorptive dressing such as Hydrofera Blue (Hydrofera Blue Classic, Hydrofera LLC, Manchester, CT) in this case. The methylene blue/gentian violet polyvinyl alcohol foam in particular has a microporous structure that is specifically designed for enhanced absorption and creates a capillary action that resembles the pulling action of negative pressure wound therapy.¹⁴ Bacteria in the exudate are drawn into the foam where the bacteria come into contact with gentian violet and methylene blue organic dyes, which work via interference with the oxidation-reduction (redox) potentials in the electron chain transport steps of oxidative metabolism and, by depleting bacterial energy, make its metabolism impossible.^15–17 Studies have supported the foam’s effective biofilm elimination (polyvinyl alcohol) and suppression of new bacterial growth.^16,17

If amputation is necessary, I try to delay it as long as is safely possible to maximize tissue salvage and move the line of demarcation to its most distal point. The current case represents my management protocol for both upper and lower extremity neonatal ischemia and gangrene injury. I believe that in all my cases this combination has saved potentially viable tissue if applied early enough in combination with the slough debridement. 

The current case is very intriguing because it may represent the first case of neonatal ischemia related to COVID-19–induced maternal coagulopathy and vasculopathy in the placental tissue. Whereas SARS-CoV-2 infections are common, maternal placental vasculopathy and potential thrombi to the infant’s vasculature should be considered in neonates born to COVID-19–positive mothers with ischemic injuries.

Dr. Boyar is Director of Neonatal Wound Services, Cohen Children’s Medical Center of New York, New Hyde Park, and Assistant Professor of Pediatrics, Zucker School of Medicine, Hofstra/Northwell, Hempstead, NY.

All photos provided are with the consent of the patients’ parents.

This article was not subject to the Wound Management & Prevention peer-review process.