Michelle K. Mcnutt
Lillian S. Kao
Presentation
A 45-year-old-man with a history of diabetes and hypertension presents to the emergency room with right leg pain and fever. His vital signs are as follows: systolic blood pressure of 90 mm Hg, heart rate of 120 beats per minute, and temperature of 101.9°F. On physical exam, his right leg has erythema extending from his ankle to midcalf. Furthermore, he has edema extending to his knee with significant pain on palpation despite cutaneous anesthesia. His laboratory values include a white blood cell (WBC) count of 18,000 with 23% bands, serum sodium concentration of 130 mmol/L, creatinine of 2.1, glucose of 300 mg/dL, and base deficit of 6 mEq/L.
Differential Diagnosis
The differential diagnosis of necrotizing soft tissue infections (NSTIs) is broad and includes nonnecrotizing cellulitis, impetigo, furuncles, carbuncles, folliculitis, skin changes of chronic venous insufficiency, insect and spider bites, or malignancy. In contrast to the other diagnoses in the differential, failure to promptly identify and treat an NSTI may result in significant short- and long-term disability, limb loss, and/or death.
Discussion
NSTIs represent a wide spectrum of diseases that can involve the skin, subcutaneous fat, superficial or deep fascia, muscle, or any combination of these structures that result in tissue death. Other descriptive terms for NSTIs include clostridial myonecrosis, gas gangrene, Meleney’s ulcer, and flesh-eating infections. Fournier’s gangrene refers to an NSTI involving the perineum. These terms all refer to an aggressive soft tissue infection that requires prompt diagnosis and surgical debridement to prevent complications such as sepsis, multiple organ failure (MOF), and death. Despite advances in medical and surgical care, the average mortality rate remains high, ranging from 10% to 23.5% in recent studies.
There are three clinical subtypes of NSTIs. Type I infections are the most common form of disease and are polymicrobial in nature. The causative microbes are a combination of gram-positive aerobes (Staphylococcus, Streptococcus, Enterococcus), gram-negative aerobes (Pseudomonas, Escherichia coli, Enterobacter, Klebsiella, etc.), anaerobes (Bacteroides, Clostridium), and fungi (Candida, mucormycoses). These organisms not only act synergistically but can also produce virulence toxins that increase tissue destruction. Type II, or monobacterial, NSTIs are frequently caused by β–hemolytic streptococci, Clostridium perfringens, and Staphylococcus aureus. Salt-water acquired NSTIs occur when a skin wound is infected with Vibrio vulnificus and are referred to as type III NSTIs. While type III infections are uncommon, these may progress rapidly to MOF and cardiovascular collapse within 24 hours and must be recognized and treated quickly.
Workup
The most important components in the diagnostic evaluation of NSTIs are a high index of suspicion and a thorough physical exam. Findings suspicious for NSTI include erythema, tense edema, vesicles or bullae, necrosis, grayish wound drainage, crepitus, ulcers, cutaneous anesthesia, and pain disproportionate to physical exam findings. Early NSTIs may present with subtle superficial findings on exam. By the time cutaneous manifestations such as blisters, bullae, crepitus, or skin necrosis are present, there may have been a significant delay in diagnosis and operative debridement. Since delay in diagnosis is associated with increased mortality, the physician must maintain a high index of suspicion during the initial evaluation. Systemic toxicity (fever, tachycardia, tachypnea, and diaphoresis) and progression of infection despite antibiotic therapy should also alert the physician to a possible NSTI.
An evaluation of past medical history is also important. While patient comorbidities such as chronic renal insufficiency, diabetes, coronary artery disease, peripheral vascular disease, and immunosuppressive conditions may serve as risk factors, NSTIs may develop in the absence of any past medical history. Other risk factors may include a history of traumatic injury, intravenous drug use, or prior surgery.
Laboratory evaluation should include an electrolyte panel, complete blood cell count with differential, and blood gas analysis. Superficial wound cultures are not helpful in directing antibiotic therapy and should not be obtained. Laboratory findings associated with NSTIs include azotemia, hypocalcemia, hyponatremia, leukocytosis, thrombocytopenia, and metabolic acidosis. A serum lactate level above 54.1 mg/dL and a serum sodium level <135 mEq/L have been associated with a higher mortality rate. C-reactive protein may be elevated as well.
Radiographic evaluation is rarely necessary to diagnose an NSTI. Soft tissue gas may be seen on plain radiographs, but the absence does not exclude the diagnosis. MRI findings of thickened fascia, fluid collection, and deep fascial rim enhancement can help differentiate NSTI from cellulitis, but should be combined with clinical findings for diagnostic accuracy. Radiographic evaluation should never delay prompt surgical debridement.
Diagnosis and Treatment
Adjunctive tests to history and physical exam findings are not necessary for the presumptive diagnosis of NSTI. The triad of crepitus, skin blistering, and radiographic evidence of soft tissue gas has a sensitivity of over 80% for the diagnosis of NSTI; thus, these three signs serve as a helpful screening tool. Rapid surgical exploration remains the gold standard for diagnosis and should be performed if NSTI is suspected. Intraoperative findings suggestive of an NSTI include thrombosis of small blood vessels (obliterative endarteritis), swollen gray fascia (liquefactive necrosis), and the ability to easily dissect fascia away from normally adherent tissue (loss of tissue planes). If the diagnosis is still uncertain, deep tissue fascial biopsy with frozen section analysis may be confirmatory. Histologic changes consistent with NSTIs include tissue necrosis, fibrinous vascular thrombosis, polymorphonuclear infiltration, and microorganisms within destroyed tissue.
The laboratory risk indicator for necrotizing fasciitis (LRINEC) score measures nonspecific biochemical and inflammatory markers and can aid in the early recognition of necrotizing infections (Table 1). A numerical score is assigned based on six laboratory parameters: C-reactive protein, total WBC count, hemoglobin concentration, sodium level, creatinine, and glucose. A score of ≥6 should raise the suspicion of necrotizing fasciitis (positive predictive value, 92% and negative predictive value, 96%), and a score of ≥8 is strongly predictive of the disease. The LRINEC score was derived from a single-center retrospective study and requires further validation with prospective studies. Despite this limitation, the LRINEC score remains a useful tool for the early detection of NSTI, and an elevated score should alert the physician to a patient at increased risk of having an NSTI.
TABLE 1. Laboratory Risk Indicator for Necrotizing Fasciitis Score
Patients with NSTI often present with systemic toxicity and vital sign abnormalities that require optimization in concert with surgical debridement. Electrolyte abnormalities should be corrected, hyperglycemia treated with insulin, intravascular volume status optimized with fluid resuscitation, and broad-spectrum antibiotics initiated. Operative exploration should not be delayed in the unstable patient. A diagnostic incision and even therapeutic exploration can be performed at the bedside in the unstable patient.
NSTI patients should be treated initially with broad-spectrum antibiotics that can then be narrowed, based on cultures. There are no data to support the use of one initial antibiotic regimen over another; however, most combinations include penicillins or cephalosporins with either an aminoglycoside or a fluoroquinolone, plus an antianaerobic agent, such as clindamycin or metronidazole. As the incidence of methicillin-resistant S. aureus NSTIs is increasing, vancomycin or linezolid may be used empirically until culture results are available. Aminoglycosides and vancomycin should be appropriately dosed and monitored in patients with renal insufficiency. Patients with cirrhosis or saltwater and seafood exposure are at increased risk for developing Vibrio infections. Vibrio is a gram-negative bacillus and is susceptible to doxycycline, as well as other antibiotics, with gram-negative activity.
Surgical Approach
Definitive therapy for NSTIs requires prompt surgical debridement and excision of all infected tissue to a margin of normal healthy tissue. This initial surgical debridement is of paramount importance and should be performed in an urgent fashion.
Since the underlying soft tissue destruction is frequently more severe than the superficial physical exam findings, the initial incision should be extensile, thus allowing the surgeon to extend the incision as necessary based upon intraoperative findings. Excision of all infected and necrotic tissue is necessary. Margins of excision should be carried out to grossly normal tissue, characterized by the lack of inflammation and purulence and the presence of normal bleeding. A tissue biopsy should be sent to pathology to confirm the diagnosis and help tailor the antibiotic regimen postoperatively. After irrigation and surgical hemostasis, the wound should be packed open with Kerlix or gauze, or, alternatively, a negative pressure wound therapy system may be used for temporary soft tissue coverage.
NSTIs may progress rapidly despite surgical debridement; therefore, most patients benefit from reexploration in 24 hours, or sooner as clinically indicated, to confirm adequacy of debridement and absence of progression. The wound is explored in the operating room on a scheduled basis, and soft tissue coverage is delayed until no further debridement is necessary. Once the wound is healthy with no progression of infection and the patient’s systemic toxicity has resolved, the wound may be closed. Wound closure may require a combination of rotational flaps and skin grafting depending on the size of the soft tissue defect (Table 2).
TABLE 2. Key Technical Steps and Potential Pitfalls in Surgical Debridement for NSTI
Special Intraoperative Considerations
In Fournier’s gangrene, a colostomy may be considered if fecal soilage is contaminating the open wound. This can be accomplished with either open or laparoscopic techniques with diverting transverse or sigmoid colostomy. With aggressive infections involving the extremities, a damage-control guillotine amputation or disarticulation may be indicated in the setting of systemic toxicity and hemodynamic instability to control the infection. Heart disease, shock (systolic blood pressure <90), and clostridial infections have been identified as three independent predictors of limb loss with NSTIs. The possibility of amputation should always be discussed with the patient or the family preoperatively.
Postoperative Management
Patients with an NSTI are best monitored in an intensive care unit setting. Aggressive fluid resuscitation and broad-spectrum antibiotic therapy should continue in the postoperative period. Continuous hemodynamic monitoring with the use of arterial and central lines may be necessary. Renal function, glucose control, and acid–base status should also be carefully monitored. Rapid clinical resolution frequently occurs following appropriate surgical debridement of the necrotic tissue, particularly if the infection is diagnosed at an early stage. Failure of resolution or clinical deterioration should raise the suspicion of progressive spread of infection and prompt a repeat exploration in the operating room.
Broad-spectrum antibiotics should be tailored to culture-specific therapy once tissue biopsy results are available and the patient has clinically improved. Antibiotics may be discontinued after clinical resolution and operative confirmation of control of infection.
The use of hyperbaric oxygen therapy (HBO) for NSTIs remains controversial. Randomized trials are lacking, and observational studies have demonstrated conflicting results. HBO cannot be recommended as routine therapy without further prospective trials. HBO may be considered with isolated clostridial infections in combination with surgical debridement, but it should never delay appropriate surgical debridement or interfere with resuscitation.
Another controversial therapy is the use of intravenous immunoglobulin for the treatment of streptococcal NSTIs. Proposed mechanisms of action involve the production of antibodies to neutralize circulating streptococcal antibodies and the interaction with proinflammatory cytokines to minimize the systemic inflammatory response. Additional studies are required before this therapy can be recommended.
Case Conclusion
The above patient was immediately treated with broad-spectrum antibiotics, insulin, and intravenous fluid resuscitation and was taken to the operating room within 6 hours of initial evaluation. All four muscle compartments were involved with infection and necrosis, and he had persistent hypotension and tachycardia in the operating room despite aggressive fluid resuscitation. A guillotine below-knee amputation was performed and he was transferred to the intensive care unit. He had four subsequent debridements and wet to dry dressings were used for temporary coverage of his wound. He required vasopressors and ventilator support initially postoperatively. He required dialysis for acute kidney failure that resolved during the course of his hospital stay. After his infection had resolved and his nutritional status was optimized, he underwent formal above-knee amputation. He was discharged home on postoperative day 16.
TAKE HOME POINTS
· The physician must maintain a high index of suspicion for prompt diagnosis.
· Delay in diagnosis and treatment increases morbidity and mortality.
· The most important therapy is immediate surgical debridement.
· Supportive therapy includes aggressive fluid resuscitation and broad spectrum antibiotics to cover gram-negative, gram-positive, and anaerobic bacteria.
· Repeat surgical debridements every 24 to 48 hours until infection is controlled.
· Mortality remains relatively high, ranging from 10% to 23.5% despite aggressive therapy.
Acknowledgments
Lillian S. Kao is supported by an NIH K23 Career Development Award (K23RR020020-05).
SUGGESTED READINGS
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Elliott DC, Kufera JA, Myers RA. The microbiology of necrotizing soft tissue infections. Am J Surg. 2000;179:361–366.
May AK, Stafford RE, Bulger EM, et al. Treatment of complicated skin and soft tissue infections. Surg Infect. 2009;10(5):467–499.
Sarani B, Strong M, Pascual J, et al. Necrotizing fasciitis: current concepts and review of the literature. J Am Coll Surg. 2009;208(2):279–288.
Wong CH, Khin LW, Heng KS, et al. The LRINEC (laboratory risk indicator for necrotizing fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. Crit Care Med. 2004;32(7):1535–1541.