Evidence-based, cost-effective management of necrotizing soft tissue infection: An algorithm of the Journal of Trauma and Acute Care Surgery emergency general surgery algorithms work group

This algorithm was developed by the Journal of Trauma and Acute Care Surgery Emergency General Surgery algorithms work group to provide an evidence-based practical approach to the initial evaluation and management of necrotizing soft tissue infection (NSTI) presenting in the emergency setting.1 The algorithm is intended to serve as a bedside reference for clinicians. It is annotated with letters linked to corresponding text that provides the rationale and references to support these recommendations. The algorithm is not a substitute for the clinical judgment and experience of bedside clinicians and should not be considered as the “standard of care.” We encourage institutions to use these recommendations to formulate local clinical protocols but recognize that patient- and institutional-specific factors may require deviation from this algorithm. Necrotizing soft tissue infection is defined as a severe and rapidly progressive skin and soft tissue infection,2,3 which is potentially life-threatening (mortality rate, 20–25%) and limb-threatening, characterized by extensive necrosis involving the skin, subcutaneous tissues, fascia and/or muscles.4–11 Soft tissue infection is a rare skin and soft tissue infection, but recent data confirm an increasing annual incidence in the United States with an annual incidence of 10.3 per 100,000 persons.12 There is wide regional/international variability in NSTI incidence, ranging from 0.6 to 15.5 per 100,000 person-years.13–15 For example, in the Netherlands, it is just 1.1 to 1.4 cases per 100,000 person-years, but it still carries a mortality of 23% to 29%, and 11% to 14% of patients require amputation for source control. Of all NSTIs, 34% to 42% were caused by group A Streptococcus (GAS). Resource utilization for NSTI treatment is high with a mean intensive care unit (ICU) length of stay of 6 to 7 days and a mean hospital length of stay of 24 to 30 days.16,17 Unplanned readmission after hospital discharge is common in NSTI patients, with recent studies reporting that 25% to 30% of patients had 90-day readmissions with a median time to readmission of 25 days.18,19 The evaluation of patients with possible NSTI in the emergency setting should focus on early diagnosis and on early surgical intervention to establish a definitive diagnosis and promptly initiate surgical debridement. NSTI DIAGNOSIS AND MANAGEMENT Early recognition of NSTIs is imperative for prompt patient management. It is estimated that approximately 50% of NSTI patients are misdiagnosed (Fig. 1).20 The diagnostic evaluation of a patient with possible NSTI first requires a thorough history and physical examination. Common presenting signs and symptoms include fever (60%), tachycardia, hypotension, soft tissue edema, erythema without sharp margins, pain out of proportion to injury, tenderness, crepitus, and cutaneous bullae or necrosis (Table 1).21 There are no widely accepted laboratory or imaging tests to confirm diagnosis of an NSTI; surgical exploration of the wound is required for a definitive diagnosis. When clinical suspicion for NSTI is high, surgical exploration should not be delayed waiting for laboratory or imaging results. Laboratory evaluation should include calculation of the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) (Table 2) and NECROSIS (Fig. 2) scores, which may be helpful but are insufficient to rule out the disease. In the index study, an LRINEC score of ≥6 had a positive predictive value of 92% and a negative predictive value of 96% for necrotizing fasciitis versus cellulitis but did not capture all NSTIs.22 A recent systematic review/meta-analysis (23 studies, n = 5,982) reported that the LRINEC score of ≥6 was 68.2% sensitive and 84.8% specific and a score of ≥8 was 40.8% sensitive and 94.9% specific.24 Since the specificity of the LRINEC score is greatest for advanced disease, there is limited sensitivity when scores are less than 6, and it should not be used to rule out NSTI.25,26 Another simple clinical index score to aid in the diagnosis of NSTI is the NECROSIS score (Fig. 2), with 1 point assigned for each variable: systolic blood pressure of ≤120 mm Hg, violaceous skin, and white blood cell count of ≥15 × 103/μL with a sensitivity of 92% for patients with at least one NECROSIS variable.23 Small studies analyzed soft tissue fluid obtained by ultrasound-guided aspiration to differentiate NSTI from cellulitis and found that lactate, lactate dehydrogenase, albumin, and total protein levels had outstanding discrimination and warrant additional study.27,28 Increased serum creatine phosphokinase levels suggest myonecrosis and are most common in NSTI caused by GAS.29 The criterion standard for diagnosis of NSTI is surgical exploration. Diagnostic imaging studies (plain radiographs, ultrasound, computed tomography, and magnetic resonance imaging) may be helpful if they demonstrate fluid along the deep fascia or gas in the tissues,30–33 but they are not sufficient to exclude the diagnosis of NSTI in cases where clinical concern is high. These patients warrant immediate surgical intervention. Radiologic studies should not delay emergent definitive surgical intervention for treatment of NSTI. There may be a role for diagnostic imaging in cases where clinical findings for NSTI are equivocal or to examine underlying disease, but the extent of NSTI tissue involvement will be determined at the time of surgery. When a diagnosis of possible NSTI has been made, early aggressive surgical debridement and surgical source control of infection are the priority and the prompt initiation of concurrent medical management. Any delay to initial surgical debridement is associated with increased mortality. Current guidelines recommend that initial surgical debridement should be done as soon as possible, ideally within 6 to 12 hours of presentation, with earlier debridement associated with improved outcomes.34–36 A recent systematic review/meta-analysis reviewed 33 studies (2,123 NSTI patients) and confirmed that mortality was significantly decreased with surgical debridement performed within 6 hours of presentation compared with >6 hours (mortality rate, 19% vs. 32%; odds ratio OR, 0.43; 95% confidence interval, 0.26–0.70). Also, surgery within 12 hours was also associated with significantly decreased mortality compared with >12 hours (OR, 0.41; 95% confidence interval, 0.27–0.61).37 Early surgical debridement lowers the NSTI mortality rate by almost 50%. Early surgical debridement is also associated with significantly reduced risk of septic shock, number of surgical debridements, and length of hospital stay.38 Repeat surgical debridements are recommended every 24 hours until there is no further evidence of progressive necrotizing infection. Complete debridement of all necrotic and infected tissue until healthy tissue with good fascial attachment is reached is the goal. Inadequate initial surgical debridement can lead to progression of the disease. Necrotizing soft tissue infection can track along tissue and fascial planes. Diagnostic NSTI findings include poor attachment of the subcutaneous tissue to the underlying fascia, fascial and tissue necrosis, purulent fluid, or the classical “dishwater fluid,” which can appear as murky gray fluid common in streptococcal infections. Thrombosed vessels in the tissue or the fascia are often seen. Fluid and tissue should be sent for Gram stain and culture for definitive diagnosis of causative pathogens and provide pathogen-directed appropriate antimicrobial therapy. The severity of NSTI should be assessed to determine whether the NSTI involves the skin (cellulitis), subcutaneous tissue (adipositis), fascia (fasciitis), and/or muscle (myositis). The exploratory surgical incision should extend to the fascia and muscle layer to determine if NSTI extends to those levels. Counter incisions may also be required to evaluate tracking of NSTI. The most common approach for NSTI surgical debridement is complete en bloc debridement, which consists of resection of all skin over the deeper affected tissue layers (fascia, muscle, subcutaneous tissue), which are also resected. This can result in very large wounds requiring reconstructive surgery. A skin-sparing debridement (SSd) technique has been recommended in which skin and subcutaneous tissue are resected only if necrotic, aiming to achieve adequate NSTI source control but limiting the skin defect and increasing primary skin closure rates.39 A systematic review of 10 studies (1 cohort study and 9 case series) reported that this technique (SSd) had no increased mortality or complication rate, no difference in length of stay, and a 75% rate of total delayed primary closure.40 However, there is potential risk of inadequate surgical debridement with the SSd technique.41 Necrotizing soft tissue infection involving the perineal region is known as Fournier's gangrene and often requires multidisciplinary surgical care.42,43 In some cases of NSTI extremity infection (up to 25%), limb amputation may be required to achieve adequate source control with surgical debridement to healthy tissue.44 Not all patients who undergo surgical intervention will have NSTI. In a retrospective single-center review of 295 patients who underwent operation for suspected NSTI, 21% had a negative exploration; this is an acceptable rate to avoid a life-threatening NSTI diagnosis.45 Intravenous fluid resuscitation should be initiated early with balanced crystalloid solutions.46 Hemodynamic support with vasopressors may also be required. Recent studies have compared more restrictive versus liberal fluid resuscitation in patients with sepsis and septic shock with no difference in mortality and reduced complications in the restrictive strategy.47,48 Based on the evidence from randomized trials to date, an individualized approach to fluid resuscitation and hemodynamic support with frequent reevaluation of cardiac, respiratory, and renal function and fluid responsiveness is optimal. Early empiric intravenous broad-spectrum antibiotics should be initiated immediately to cover all potential polymicrobial pathogens. Fluid and tissue cultures from the OR should be obtained for definitive diagnosis of causative pathogens and antimicrobial susceptibilities to enable pathogen-directed appropriate definitive antimicrobial therapy. In a recent systematic review of 27 studies (n = 2,242 patients), polymicrobial infections (52.2%) were more common than monomicrobial infections (39.9%), with most monomicrobial infections related to extremity NSTI.49,50 Therefore, initiation of early empiric antimicrobials to cover polymicrobial NSTI, with activity against gram-positive (including Methicillin-resistant staphylococcus aureus), gram-negative, and anaerobic bacteria, and antitoxin antibiotics (clindamycin or linezolid) is imperative (Table 3). Pathogen-directed antimicrobial therapy is optimal once operative cultures are available for review and the definitive bacterial etiology of NSTI is known with antimicrobial susceptibilities. Classification of NSTI (four types) is based on the causative pathogens identified (Table 3) from surgical cultures obtained at the time of surgical debridement. Polymicrobial (Type I) NSTI are most common, followed by Type II monomicrobial (GAS and Methicillin-resistant staphylococcus aureus) NSTI. Rare bacterial etiologies of NSTIs include Type III (clostridial and aquatic bacteria such as Vibrio and Aeromonas). Type IV NSTI is fungal in etiology, including candida or zygomycetes, and is most common in military combat casualty wounds with invasive fungal infections.51 Antimicrobial treatment should continue until adequate surgical debridement is complete, the wound has no evidence of infection, and the patient is clinically improving. At present, no randomized clinical trials have evaluated the optimal duration of antibiotic therapy for NSTI. A systematic review and meta-analysis of four observational studies (n = 532 patients) reported no difference in mortality (5.6% vs. 4.0%) or limb amputation comparing short (≤7 days) versus long (>7 days) antibiotic duration for NSTI, but the overall mortality rate and sample size were both low in this report.52 Septic shock is common in NSTI patients, and appropriate septic shock management should be immediately initiated based on the 2021 International Guidelines for Management of Sepsis and Septic Shock.53,54 Toxic shock syndrome can occur with both staphylococcal and streptococcal NSTI, is associated with a significantly higher mortality rate, and requires antitoxin and potentially additional supportive therapies. All NSTI patients should be evaluated for potential need for ICU admission. Patients with NSTI associated with organ dysfunction should be admitted to the ICU, as they are at higher risk for the development of worsening organ dysfunction and/or failure. In addition to fluid resuscitation and organ support, these patients may require intubation and mechanical ventilation, renal replacement therapy, and cardiac support with vasopressors and cardiotonic drugs. The routine use of adjunctive therapies (intravenous immunoglobulin IVIG and hyperbaric oxygen HBO) is not recommended. Adjunctive therapies for NSTI treatment may be considered in patients who are not improving or progressing with standard therapy. Some guidelines and experts recommend IVIG as an adjunctive treatment for streptococcal toxic shock syndrome because of its beneficial effect of neutralization of superantigens and toxins and enhanced bacterial clearance.1 Observational studies report that IVIG may be beneficial in patients with streptococcal NSTI and toxic shock syndrome.55 A meta-analysis of one randomized controlled trial and four observational studies reported a significant reduction in mortality from 33.7% to 15.7% (Relative risk, 0.46).56 A small, randomized trial Immunoglobulin G for patients with necrotising soft tissue infection (INSTINCT) compared IVIG with placebo in 100 patients with NSTI found no impact on patient outcomes but used a low IVIG dose and was not specific for streptococcal NSTI.57,58 A retrospective cohort study using the Vizient database evaluated IVIG use in patients with necrotizing fasciitis and vasopressor-dependent shock and found no impact on mortality or length of stay.59 A recent Cochrane review could not draw conclusions regarding the effect of IVIG on 30-day mortality or serious adverse events because of the very low quality of the evidence.60 Intravenous immunoglobulin can be considered for patients with GAS NSTI and streptococcal toxic shock syndrome based on the currently available evidence. Two recent meta-analyses of observational studies and a retrospective study of HBO therapy for NSTI reported significantly lower mortality rates (Relative risk, 0.44–0.52) with no difference in amputation rates.61–63 A Scandinavian multicenter prospective observational cohort study (the Improving Outcome of Necrotizing Fasciitis: Elucidation of Complex Host and Pathogen Signatures that Dictate Severity of Tissue Infection study) enrolled NSTI ICU patients (n = 409) and reported that the use of HBO was associated with reduced 30-day all-cause mortality.64 Other studies show no benefit to HBO therapy for NSTI.65,66 Hyperbaric oxygen is therefore not consistently recommended in guidelines for NSTI but can be considered if available. An initial core set of outcome measures for NSTI research has been proposed by an international multidisciplinary modified Delphi consensus study, which will facilitate future research in this area.67 Optimal wound care is important following surgical debridement of NSTI. Since randomized clinical trials are lacking in this area, there is currently no consensus regarding optimal wound care. It is important to ensure that the chosen wound dressings minimize pain and allow patient mobility. Negative pressure wound therapy (NPWT) after surgical debridement of all infected tissue is less painful than frequent dressing changes, and multiple studies report higher rates of wound closure and survival compared with conventional care.68,69 Granufoam silver NPWT has proven high concentration of silver in wound exudate and antimicrobial effects against Staphylococcus aureus,70,71 but no comparative randomized studies in NSTI are available. Similarly, NPWT with instillation, which combines negative pressure with a topical wound solution instilled intermittently into the wound bed, was associated with higher rates of wound closure in NSTI patients compared with traditional NPWT or moist wound care dressings.72,73 Once surgical debridement of NSTI is complete and healthy tissue is evident in the open wound, planning for definitive wound closure should begin. In many cases, if a skin sparing technique40,74 is used at the time of NSTI surgical debridement, it is possible to perform delayed primary closure of the open wound, facilitated with NPWT. Additional options for wound closure include tissue expanders, skin grafts, fish skin xenografts,75 biodegradable temporizing matrix,76,77 and advancement or free flaps. Figure 1: Management algorithm for NSTI. CBC, complete blood count; CRP/ESR, C-reactive protein/erythrocyte sedimentation rate; H IV, intravenous. TABLE 1 - Signs and Symptoms of NSTI Sign/Symptom Percentage of Patients at Presentation Bullae 26% Skin necrosis 24% Crepitus 20% Gas on x-ray evaluation 25% Swelling 81% Pain or tenderness 79% Erythema 71% Warmth 44% Fever 40% Hypotension 21% Adapted from Ref. 21. TABLE 2 - Diagnosis of NSTI According to the LRINEC Score LRINEC Score Variable Score C-reactive protein, mg/L 25 2 Hemoglobin, g/dL >13.5 0 11–13.5 1 141 2 Glucose, mmol/L ≤10 0 >10 1 The maximum LRINEC score is 13; a score of ≥6 should raise the suspicion of necrotizing fasciitis, and a score of ≥8 is strongly predictive of NSTI. Laboratory Risk Indicator for Necrotizing Fasciitis score, from Ref. 22. Figure 2: Diagnosis of NSTI according to the NECROSIS score. One point is assigned for each variable: systolic blood pressure of ≤120 mm Hg, violaceous skin, and white blood cell count of ≥15 × 103/μL with a sensitivity of 92% for NSTI diagnosis in patients with at least one NECROSIS variable. NECROSIS score, from Ref. 23. TABLE 3 - Classification of NSTI Based on Causative Pathogens and Empiric Antibiotics Type Causative Pathogens Risk Factors, Features Initial Empiric IV Antimicrobials* Type I Polymicrobial: most common NSTI overall Older patients with multiple comorbidities, diabetes Gram negative: β-lactam/β-lactamase inhibitor (piperacillin-tazobactam), carbapenem, or cephalosporin (cefipime) and anti-anaerobic agent (metronidazole)Gram positive including Methicilliln-resistant staphylococcus aureus: linezolid or vancomycinAntitoxin: linezolid or clindamycin Type II Monomicrobial: GAS, most common pathogen; MRSA, second most common pathogen; MSSA, less common pathogen Trauma, surgery, IV drug use; associated with toxin production, can cause toxic shock syndrome GAS: high-dose penicillinMRSA: linezolid, vancomycin, daptomycinMSSA: cefazolin or oxacillin Type III Monomicrobial: Vibrio, Aeromonas, Clostridium spp. Contaminated water exposure, aquatic pathogens Vibrio/Aeromonas: third-generation cephalosporin (cefipime) plus doxycycline or fluoroquinolone Clostridium: high-dose penicillin Type IV Fungal organisms: Candida or zygomycetes Immunocompromised hosts, military trauma Candida: micafunginMold/Aspergillus: amphotericin B *If septic shock or toxic shock is present, add antitoxin therapy with either linezolid or clindamycin. Pathogen-directed antimicrobial therapy should be initiated after identification of causative NSTI pathogens via microbiological cultures.Adapted from Open Access:Charlier C, Souhail B, Dauger S, Woerther PL, Bleibtreu A, Caseris M, C, C, A, B, therapy in necrotizing soft tissue a review of the A, antibiotic and duration in NSTI