This review aims to analyze the role of specific diagnostic and therapeutic interventions that have a positive impact on the necrotizing soft tissue infection approach, in a timely manner way to prevent death of the patient, as well as to avoid limb loss. We discuss the usefulness of clinical findings, imaging, and biochemical markers in the address of the infection. In addition we present and analysis of hyperbaric oxygen therapy in the role of these infections.

Keywords: necrotizing soft tissue infections, gas gangrene, hyperbaric oxyge n, necrotizing fascitis, magnetic resonance imaging, clostridial myonecrosis

Necrotizing soft tissue infections (NSTIs) are a group of clinical entities characterized by progressive and fulminant destruction of rapidly evolving tissues, associated to high mortality rates due to systemic toxicity and multiorgan failure.¹ The microbiological classification of NSTIs by subtypes is very useful to review therapeutic and diagnostic schemes. Type 1 is the most prevalent, comprising polymicrobial infections by aerobic and anaerobic bacteria. The predominant isolates are species of the Streptococcus, Staphylococcus, Enterococcus, Pseudomonas, Acinetobacter, Bacteriodes generas and members of the Enterobacteriacea family. Clostridium commonly participates in this context without causing myonecrosis. Events that compromise peripheral vascularization are the classic risk factor for acquiring the infection, where interestingly, no triggering events where identified in 20-50% of patients.² The Fournier Gangrene, diabetic foot infection and necrotizing fasciitis are classic infections of this group. It also includes complications of odontogenic infections caused by Fusobaterium, Peptostreptococcus, Bacteriodes, anaerobic Streptococcus and spirochetes.^1–2 Type 2 infections are monomicrobial caused by Streptococcus group A, some are accompanied by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). Unlike the first group, these can occur in patients without predisposing factors.^1–2

Finally, type 3 includes monomicrobial infections attributed to Clostridium, Vibrio vulnificus or Aeromonas sp. The first one have a strong association to trauma and surgeries. With the improvement in surgical interventions, the current epidemiology has changed to injuries in patients with intravenous (IV) drug abuse. Clostridium perfringens is the etiologic agent in 70-80% of cases. The remaining genera are associated with similar infectious processes. The exhaustive approach in the clinical history is necessary to establish differential diagnosis, specifically to investigate contact with different types of water.^1–2

The key to the timely therapeutic approach of NSTIs is early diagnosis. It is imperative to recognize them early, since delays in the approach have a high association with extensive tissue destruction and consequent loss of limbs^1–2 However, the clinical presentation is not clear; there is usually absence of classic signs and symptoms. The treatment strategy includes antimicrobial therapy and serial and aggressive surgical debridement.^1–3 There is a flow of information on complementary techniques to this basic therapy, such as the therapeutic strategy of hyperbaric oxygen (HBO), blood infusions and intravenous immunoglobulins. In turn, there are multiple published clinical guidelines for comprehensive management, however; its application is limited.² This review aims to analyze the role of specific diagnostic and therapeutic interventions that have a positive impact on the INTB approach, in the time and manner to prevent the death of the patient, as well as to avoid limb loss.

Despite the difficulties presented by the patient's exploration, this process is crucial to establish an opportune diagnosis. It is important to note that the positive predictive value (PPV) of pathognomonic physical findings isn´t surpassed by any other technology.^1–4 The localized pain is perhaps the symptom of first appearance; it can be accompanied by erythema, hyperthermia, edema around the erythematous zone, epidermolysis, tachycardia, fever and tanning of the skin. Late physical findings include hemorrhagic bullae, bad odor, dermal gangrene, crepitus, seropurulent drainage, inflammatory response syndrome and progression of early symptoms. The disproportionate pain of sudden onset is highly suggestive of NSTIs, unfortunately, at this level the tissue involvement is already large and irreversible, with imminent amputation of the affected limb in most cases.^2–4 Tissue involvement in the same way is variable, ranging from subcutaneous necrosis to sepsis with injuries in fascia and muscles. Although, it methods for early detection from serological markers have been proposed. The laboratory risk indicator for necrotizing fasciitis (LRINEC) is a strategy that considers C-reactive protein, white blood cell count, hemoglobin concentration, sodium, creatinine and serum glucose to establish a risk score.⁵ The above parameters are integrated in a risk indicator of necrotizing fasciitis.⁵ This indicator has had limited acceptance by the medical community, which suffers from the lack of correlation with reality, where leukocytosis and hyponatremia do not occur simultaneously. It is important to note that this tool was developed exclusively with laboratory parameters ignoring physical findings; in this sense, it is difficult to reproduce results in the scenario of a disease with such variability in its clinical presentation. In addition, when there is a high suspicion of necrotizing fasciitis throughout the history, physical examination, LRINEC should not be calculated. The clinician will go directly to surgical debridement. In summary, the approach with biochemical scores has utility in the exclusion of NSTIs, but not in its identification. A high index of clinical suspicion remains the paramount.⁵

The scope of microbiological studies in the early diagnosis of NSTIs is limited. The aspiration of fluid for detection of microorganisms in initial stages has low VPP.¹ Additionally, the presence of bacteria does not always correlate with the infectious process from this sample. In fact, absence of drain does not rule out tissue commitment either. Gram staining can be definitive in the diagnosis of some NSTIs. However, the sample that presents adequate sensitivity is the tissue obtained during the surgical exploration.^1–2 Therefore, this intervention does not contribute to early diagnosis. Cultures take a long time to complete, so that few authors consider them in algorithms of action.^1–3 Therefore, microbiological techniques are not considered interventions with timely clinical impact.

In patients with physical findings that do not support urgent debridement, imaging techniques can clarify tissue involvement and define whether the clinical picture corresponds to NSTIs.⁶ However, it should not be forgotten that in the presence of clear signs and symptoms, surgical intervention without any delay of images is mandatory. NSTIs are characterized by massive destruction of tissues; the initial presentation can be restricted to deep planes, leaving the skin intact.^2–5

It is important to consider that there is no universally accepted imaging protocol to address patients with suspected NSTIs.⁶ Techniques such as computed tomography (CT), flat X-rays and magnetic resonance imaging (MRI) have been used, but none of those is the gold standard.^6,7

The use of images seeks to demonstrate pathognomonic and complementary features that guide the diagnosis of NSTIs. In this sense, flat X-rays are excluded from the scenario, as they rarely show the presence of gas. Previous studies reported the finding in 25-47.7% of patients. Although this characteristic is of variable appearance, it has high specificity for the diagnosis. The current use of simple X-rays is limited to ruling out underlying bony lesions or the presence of foreign bodies.⁶

Previously, CT was questioned because of its low sensitivity and specificity in the diagnosis of necrotizing infections.¹ However, most studies were based solely on gas detection. This finding has a great impact for the early detection of gas gangrene. Clinical signs and symptoms such as subcutaneous crepitus and disproportionate pain of the extremity added to the presence of gas in subcutaneous tissue is pathognomonic of the Clostridial infection. Therefore, previous reports restricted the use of CT only to address this particular NSTI.^1–6 Its capacity to guide the diagnosis of the spectrum of necrotizing infections has increased significantly with updated technology, introduction of contrast media and updating of criteria.⁷ The observation of inflammatory changes under fascias, presence of multiple fluid collections and unequal contrast medium distribution has been incorporated⁷ With the inclusion of these variables, high sensitivity and Negative Predictive Value (NPV) are obtained, in one study 100% was reported for both parameters, suggesting its use to reliably rule out the need for surgical intervention in patients with high suspicion of NSTIs. ⁷

A score for the diagnosis of NSTIs based on CT have been proposed. The presence of gas in the fascia, muscular edema, fluid collection, lymphadenopathy and subcutaneous edema is contemplated.⁴ The developer research group has shown striking evidence, however the studies carried out were retrospective, including patients without NSTIs as control group,⁸ this approach introduce significant heterogeneity. ⁴ In addition to its diagnostic value, CT can help in the planning of surgical exploration of the suspicious area, especially in the presence of extensive edema or involvement of difficult anatomical areas, such as the retroperitoneum or mediastinum.⁷ This is intended to debride all affected areas and avoid further complications. Deep abscesses are approached correctly with CT, contrary to clinical examination where they can go unnoticed.¹

Magnetic resonance imaging (MRI) can accurately differentiate necrotizing infections from non-necrotizing infections.¹ Due to its high spatial resolution and inherent contrast, the technique provides accurate information on anatomical compromise, at the level considered by some as the modality of image of choice to evaluate anomalies in the musculoskeletal system, including infection.⁹ The findings allow clinicians to confirm or exclude the diagnosis of NSTIs, in addition to clearly establishing the distribution and margins of the commitment. With this technique, multiplanar images can be obtained without the use of ionizing radiation, which is an advantage when using TC.⁹

Unfortunately, the time invested taking images for MRI does not justify its use, especially in a patient with sepsis who may be subjected to other procedures simultaneously.^1–2 Additionally, these scans require complete immobilization, where any movement can lead to exhaustive and unproductive interpretations, in a way that would further delay the diagnosis.⁷ On the other hand, MRI is not as useful as CT for the detection of gas in soft tissues. This technique tends to overestimate the involvement of deep tissues; therefore, it cannot be used to reliably distinguish between necrotizing cellulitis and deeper infection.^7–9

Tissue biopsies provide reliable results in NSTIs. It is based on the observation of histological changes that include tissue necrosis, polymorphonuclear infiltration, vascular thrombosis and sometimes microorganisms within the destroyed tissue. Despite providing valuable information, clinical experience is limited, since the pathology professional is not available 24 hours a day to perform the interpretation in the time and manner required.^1–3

Once the diagnosis of NSTIs is establish, the initiation of the classic treatment can be complemented with alternative therapies, such as exposure to hyperbaric oxygen (HBO). This consists of oxygen administration under pressure that exceeds 1 absolute atmosphere, achieving dramatic increase in oxygen tension within the tissues. The benefits are direct bactericidal/bacteriostatic activity, optimization of the immune response and additive or synergistic effect with antimicrobials. The main target are species of anaerobic bacteria; they have few detoxification mechanisms against reactive oxygen species.^10,11

The increase in oxygen tension enhances host defense mechanisms, particularly the bactericidal activity of neutrophils. Although the degranulation of polymorphonuclear cells can operate in a hypoxic state, the induction of death due to oxidative damage is totally dependent on oxygen, which is why the requirement for this element increases up to 15 times during NSTIs. On the other hand, in the pathogenesis of gas gangrene and streptococcal myonecrosis, the increase in the adherence of neutrophils to cells of the vascular epithelium promotes the establishment of hypoxia, and with the survival of the pathogen.^10,11

Regarding the action of antimicrobials, the synergy of HBO with antibiotics directed to treat infections caused by aerobic bacteria has been exhaustively demonstrated. The higher the concentration of dissolved oxygen, the optimal levels for action of aminoglycosides, fluoroquinolones, trimethoprim-sulfamethoxazole, vancomycin and some sulfonamides. However, this potentiation have limited effect against anaerobic bacteria implicated in most INTB. ¹¹ The incorporation of HBO in clinical guidelines is subject to gas gangrene, necrotizing fasciitis, diabetic foot infections, refractory osteomyelitis, neuro surgical infections and some fungal infections. Like MRI, this approach cannot be applied in patients who require multiple interventions at the same time, especially in scenarios of medical emergencies. The time of transfer to the hyperbaric chamber and delay by pressure compensation should also be considered.^10,11 HBO should never be used in monotherapy for NSTIs.^1,3,10,11 It is indicated in the cases mentioned as complementary therapy, included in clinical guidelines of the Hyperbaric Medical Society and the European Committee of Hyperbaric Medicine.² The literature indicates that HBO inhibits the reproduction of Clostridium and production of new toxins, as well as detoxification of circulating toxins.¹⁰ In addition, exposure to prolonged oxygen prevents tissue loss and promotes wound healing. These properties suggest recommending therapy for gaseous gangrene; it is complementary and does not replace surgical debridement. The proposed approach suggests starting with HBO, then entering the operating room to remove necrotic tissue. This sequence has proven to be beneficial, since it easily demarcates the affected area and establishes a better limit for debridement.¹¹The antimicrobial treatment should be initiated as soon as possible. On the other hand, necrotizing fasciitis can be treated with HBO to extend the patient's survival, being a complementary therapy to first-order interventions such as surgical intervention and antimicrobial therapy. Subsequent sessions in the hyperbaric chamber are required to avoid re-entry to the operating room and reduce the healing time.¹¹ In diabetic foot infections, HBO has been indicated in chronic cases that do not heal with aggressive treatments. Some medical centers prescribe this therapy to patients with Wounds grade Wagner III or higher, who present a failure in a standard 30-day scheme consisting of correction of vascularization, optimization of nutritional status, glucose control, surgical debridement and antimicrobial treatment.¹⁰ The controversy with HBO lies in the absence of properly conducted clinical trials, with cases and controls that demonstrate clinical efficacy. ² The studies published to date only support its use in NSTIs type 1 (polymicrobial), in type 2 and 3 only 2 is recommended. It is necessary to consider that the conduct of randomized trials in conditions such as gas gangrene is not possible, since it is not considered ethical to use a control group, as there is theoretical evidence of benefit with the use of HBO in anaerobic infections. Additionally, there is little information that specifies the standardized time of exposure, timely application during the course of the infection, days of therapy, among others. A report reports that the application protocol must be continued until the control of the infectious focus and resolution of physiological abnormalities.^2,10,11

Reporting side effects during HBO is unusual and requires minimal treatment. Barotraumas, defined as trauma induced by pressure in the middle ear, are a recognized self-limited complication, they occur mainly in the patient with assisted mechanical ventilation. The worst scenarios have been reports of acute cerebral toxicity due to oxygen accompanied by seizures.¹² The purification of blood by plasmapheresis is another therapeutic strategy of great utility in the treatment of NSTIs. It is based on the removal of molecular mediators proposed as causal of the pathophysiology of INTB and its consequent sepsis.² Deep hypoalbuminemia is also common, therefore, substitution with colloid (albumin) may be necessary to maintain oncotic pressure. Red blood cell transfusions due to extravascular hemolysis generated by the effect of bacterial toxins. Bacterial hemolysins cause surprising and rapid reductions in the hematocrit in the absence of disseminated intravascular coagulopathy. Therefore, the hematocrit may be a better indicator of the need for transfusion than the level of hemoglobin.^1–3

The NSTIs continue to present a diagnostic challenge in daily clinical practice. Current radiological techniques have shown to guide surgical exploration, generating a significant impact on the survival of the patient. Due to its characteristics, CT is the most feasible method to incorporate into diagnostic algorithms. The use of HBO has been widely explored as an adjunct to conventional therapy; however, clinical data only support its use in type 1 INTB. These and other strategies can be incorporated in the approach of these clinical entities, being clear their role as complement to the basic action plan, which includes diagnosis based on exhaustive physical examination, antimicrobial administration and surgical debridement. The early application of these measures is crucial to ensure patient survival.

None.

The authors declares there is no conflicts of interest.

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