- Email: [email protected]
Necrotizing Soft-Tissue Infections
SURGICAL INFECTIONS
0039-6109/94 $0.00 + .20
NECROTIZING SOFT-TISSUE INFECTIONS Mark E. Sutherland, MO, and Anthony A. Meyer, MO, PhD
Necrotizing soft-tissue infections continue to challenge the practicing surgeon. These infections represent a diverse disease process; the term itself encompasses a continuum ranging from simple pyodermas to life-threatening infections. They vary in regard to anatomic location, tissue level of involvement, predisposing conditions, and offending organism(s). These factors, together with contributing factors of the host, result in a variety of presentations and subsequently affect the clinical course and prognosis. Consequently, this has led to the use of a variety of terms in the literature. Historically, the entity was known as hospital gangrene36 during the US Civil War. A variant of the disease has become known as Fournier's gangrene, after a necrotizing infection of the perineum was described by Fournier in 1884.24 Many gangrenous infections of the skin and soft tissues were labeled Meleney's gangrene following Meleney's description of acute hemolytic streptococcal gangrene46 and the synergistic association of anaerobic streptococci and staphylococci.46 Wilson64 preferred the term necrotizing jasciitis, finding fascial necrosis to be the most consistent manifestation of the disease. Clearly the term gas gangrene has served more to confuse than to clarify. Although this term was used initially to denote deep clostridial infections, the majority of gas-producing infections are caused by nonclostridial organisms, and a number of noninfectious processes may be responsible for the development of subcutaneous emphysema. It stands to reason that classification based upon the organism or tissue level involved would add to the confusion, as this information is rarely available preoperatively. From the Department of Surgery, Tulane University Medical Center, New Orleans, Louisiana (MES); and the Department of Surgery, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina (AAM)
SURGICAL CLINICS OF NORTH AMERICA VOLUME 74· NUMBER 3· JUNE 1994
591
592
SUTHERLAND & MEYER
Conceivably, this confusion may result in delay in both proper diagnosis and appropriate treatment, a disconcerting thought when one realizes that a time-honored surgical dictum remains true for necrotizing soft-tissue infections-early diagnosis along with rapid and aggressive surgical intervention reduces the associated morbidity and mortality of the disease process. Recognizing this, Baxter4 separated the infections based on the need for and extent of surgical intervention required to control the infection and optimize patient outcome. This confused state of terminology has led to difficulties in understanding the disease process. The various factors and generalities of this disease process are reviewed, as well as specific characteristics of the more common and discrete entities included under the umbrella diagnosis of necrotizing soft-tissue infections. A conscious effort is made to avoid the haphazard use of nonstandardized terminology.
PRESENTATION AND DIAGNOSIS
A patient presenting in florid sepsis with obvious skin involvement requires more thought with regard to treatment than to diagnosis. Conversely, one who presents with minimal cutaneous manifestations of necrotizing soft-tissue infection requires a high index of suspicion in order to make an early diagnosis. This can be extremely difficult when the infection occurs spontaneously, without history of an antecedent event. Recognizing predisposing factors of the host may assist the clinician, as the majority of patients have at least one of several co-morbid conditions. This includes chronic disease states such as diabetes mellitus, peripheral vascular disease, and parenteral drug use. Diabetics have premature small vessel abnormalities that limit blood flow and delivery of oxygen, leukocytes, and antibiotics. They also have an inherent neutrophil dysfunction, manifested by impaired phagocytosis and chemotaxis. This can be compounded by the presence of a functional neuropathy such that the usual initial symptom-pain-is not experienced by the patient, allowing the infection to progress. Other underlying disease states may include alcoholism, malnutrition, and AIDS. The patient may also be immunocompromised by malignancy or the administration of chemotherapy, resulting in granulocytopenia. The steroid-dependent chronic obstructive pulmonary disease patient, as well as the transplant recipient, is also at risk. Patients who have suffered severe injury have an increased incidence of infection secondary to breaks in the skin barrier, the presence of a foreign body, devitalized tissue, or a fluid collection-especially blood. Tissue edema, secondary to disruption of normal lymphatic flow or venous drainage, can also increase the risk of infection. Although the clinical course of the infectious process is influenced by the above factors, it also depends upon the virulence of the microbe and size of the inoculum. Thus, a variety of presenting signs and symp-
NECROTIZING SOFT-TISSUE INFECTIONS
593
toms have been described.* The physician must be aware that necrotizing soft-tissue infections may complicate even the most minor elective procedure, emergency procedure, or traumatic injury. Deep tissues may be the initial focus of the infectious process, with secondary skin involvement. Conversely, the fascia and muscle may become involved with invasion of what began as a superficial infection. An apparent cellulitis that fails to respond to standard therapy-appropriate antibiotics, elevation, immobility-must raise suspicion of more extensive infection. Classically, necrotizing soft-tissue infections present initially with localized pain and a deceptively benign appearance. I, 4,15,37 Dermal involvement becomes apparent as the infectious process spreads along fascial planes. Local signs of deep tissue infection may include cyanosis or bronzing of the skin. An example of this bronzing is shown in Figure 1. Induration becomes evident and is one of the most constant physical findings, Crepitance is present when the infection includes a gas-producing organism. As the inflammatory process causes thrombosis of the perforating vessels to the skin, epidermolysis or dermal gangrene may be seen. Sensation of the overlying skin can vary from severe pain to paresthesias and even anesthesia. In the extremity, decreased range of motion eventually occurs. Concurrently, systemic manifestations of sepsis develop-altered mental status, tachycardia, tachypnea, leukocytosis, *References 1, 4, 14, 15, 20, 30, 37, 39, 50.
Figure 1. A 62-year-old man with a necrotizing infection of the left leg. Note the bronzing of the skin over the calf.
594
SUTHERLAND & MEYER
hyperglycemia, oliguria, fever/chills, and metabolic acidosis. Bacteremia is rare, identified in only 11% of patients in one series. 22 These signs and symptoms are summarized in Table l. Radiographic studies seldom offer additional information. Plain films may reveal air in the soft tissues,22 the presence of a foreign body, or osteomyelitis in the underlying bone. Although gas in the tissue is a nonspecific finding, its presence should alert the clinician to the possibility of severe infection. Ultrasound or CT scan may be helpful on occasion for some deep infections when they identify air or extensive soft-tissue edema (e.g., retroperitoneal infection from diverticulitis). Nuclear medicine scans such as indium or gallium scans require too much time to obtain results to be of significant value. Wilson64 recommends attempts to pass a probe or a finger through an incision or opening in the skin along the plane just above the deep fascia to assess the presence and extent of undermining, a manifestation of subcutaneous and fascial necrosis. He thought that this separation at the fascia was a pathognomonic feature of the disease process he termed necrotizing jasciitis. Whenever the diagnosis is considered, it is best to either confirm or exclude a deep tissue infection with direct visual examination of the underlying muscle and fascia. Stamenkovic and Lew 59 stated that they were able to diagnose the presence of necrotizing fasciitis within an average time of 21 hours after the onset of symptoms by the use of frozen tissue sections. However, clinical presentation, suspicion of the presence of a necrotizing softtissue infection, and operative exploration remain the best diagnostic maneuvers. Most surgeons who have experience with necrotizing softtissue infections can make the diagnosis more rapidly in the operating room.
GENERAL PRINCIPLES OF TREATMENT
Kaiser and Cerra,37 as well as Dellinger,15 have recognized necrotizing soft-tissue infections to be "variations of the same disease process" and suggest that they be managed by means of a unified approach, in which all soft-tissue infections are treated as potentially life-threatening emergencies. The first tier of management requires aggressive resuscitative measures, often assisted by invasive monitoring in the surgical ICU. While correction of the metabolic derangement is begun, all other organ systems are assessed and supportive measures instituted if necessary. Concomitantly, broad-spectrum antibiotics are administered, and the tetanus status is reviewed and updated as needed. Empiric antibiotic coverage typically entails penicillin-G (3 million units every 4 hours), an aminoglycoside or a third-generation cephalosporin, and possibly clindamycin or metronidazole for additional anaerobic coverage. The choice of penicillin-G reflects the 60% to 70% incidence of Group A f3-hemolytic streptococci in these wounds. The wound should be explored expeditiously in the operating room.
NECROTIZING SOFT-TISSUE INFECTIONS
595
Table 1. SIGNS AND SYMPTOMS OF NECROTIZING SOFT-TISSUE INFECTIONS Local signs Inflammation Pain Swelling Redness or bronzing Warmth Loss of function Induration Cutaneous blistering or necrosis Induration Crepitance Persistence or progression of inflammation despite appropriate therapy Systemic signs Obtundation Fever or hypothermia Leukocytosis or leukopenia Shock Multiple organ dysfunction or failure
Even if a patient remains in septic shock after resuscitation and antibiotics are begun, surgical debridement should not be delayed. In such situations, correction of the septic state does not occur until the infection is excised. Delay only worsens outcome. The incision is made directly over the area of skin involved or the most indurated region. The skin incision(s) should be parallel to the neurovascular bundles and carried down to fascia. The underlying muscle and fascia are inspected; all necrotic tissue is excised in all directions to healthy viable tissue. Debridement is considered adequate when finger dissection can no longer easily separate the subcutaneous fat from the fascia. One should be reluctant to leave overlying flaps of skin and subcutaneous tissue, as these may hinder proper evaluation of the wound postoperatively and thereby delay further debridement. When burrowing areas of necrotic fat are absent and necrotizing fasciitis has been excluded, the skin flaps may be preserved because tissue cellulitis resolves rapidly with proper treatment, leaving viable skin. Tissue and fluid specimens should be obtained from beneath intact skin, well away from any open wound. This should be sent for Gram stain as well as aerobic and anaerobic cultures with sensitivities. The wound is packed open and kept moist with saline. Antibiotic solutions have not been found to be necessary, and some stain the tissue and prevent inspection for necrosis. The patient should be returned to the operating room every 24 hours until progression of the necrosis is halted. Failure to re-explore the wound can lead to progression of the infection to previously healthy tissue, as seen in Figure 2. Further daily exploration under general anesthesia is especially recommended for truncal infections and for all patients who remain clinically septic. Postoperatively, these patients often require leu care so that cardiac, pulmonary, renal, and metabolic systems can be monitored and opti-
596
SUTHERLAND & MEYER
Figure 2. A 23-year-old man 3 days following debridement of a right antecubital infection without subsequent re-exploration. Note the progressive cellulitis and pitting edema on the chest wall.
mized. Choice of antibiotics is based on identification and sensitivity of the organism(s) isolated. Early enteral nutritional support is clearly beneficial in these patients. If this route is not tolerated, parenteral nutrition should be administered. Many patients benefit from a specialized bed to prevent skin breakdown. It is also helpful to institute physical and/or occupational therapy at an early stage once sepsis has resolved. Many authorities 1• 15 are reluctant to cover the site until they are assured that the infection is completely resolved. At that time, skin grafts are applied to granulation tissue, and free or rotational soft-tissue flaps are used to cover exposed bone, cartilage, tendons, and neurovascular structures. This should be done as soon as possible to preserve function and prevent wound problems.
STREPTOCOCCAL INFECTIONS
Group A streptococcus (Streptococcus pyogenes) can inflict disease in several organ systems, and infection of the soft tissues can occur at any leveP9 These organisms are the most common cause of necrotizing softtissue infection. The more benign forms include cellulitis, lymphangitis, and impetigo, and the more severe forms include erysipelas, necrotizing
NECROTIZING SOFT-TISSUE INFECTIONS
597
fasciitis, and streptococcal myositis. As previously stated, this latter entity was described as streptococcal gangrene by Meleney in 1924. 46 It has since acquired other names such as necrotizing erysipelas. Currently, a streptococcal toxic shock-like syndrome has evolved. 12 ,65 With an increase in the incidence of streptococcal infections being noted, it is feared that the organism may be acquiring greater virulence. l l Conditions that predispose to streptococcal infections include intravenous drug abuse, atherosclerotic vascular disease, and any immunocompromised state. Invasive streptococcal infection affects all ages from neonates to geriatric patients and can follow minor or major trauma. It has also been reported following a varicella infection. ls Perhaps the most alarming aspect of streptococcal infection is its ability to cause severe disease in otherwise healthy patients, whereas clostridial and mixed facultative-anaerobic infections have a predilection for debilitated hosts. The classification of the various strains of streptococci depends upon the type of M protein, a surface protein allowing the organism to adhere and colonize, the first step in gaining a foothold leading to invasion. It also helps the organism to evade phagocytosis by neutrophils in the absence of type-specific antibody. The pathogenicity is derived from the production of a variety of extracellular substances-cytotoxins, streptokinase, hemolysins, and pyrogenic exotoxins A, B, and C. The toxins may damage tissues by a direct effect upon the cells or indirectly by stimulation of the monocytes to produce an inflammatory response. The infection spreads along fascial planes and/ or through muscle groups. The streptococcal toxic shock-like syndrome was first postulated in 1983. 63 It consists of hypotension, fever, rash, desquamation, and multiorgan-system dysfunction. In reviewing the literature, Wood and co-workers65 found more than 50 reported cases. The patients' ages ranged from 14 months to 76 years, and the majority were female (68%). Although the leading sites of infection were the skin and soft tissues, 12 patients had mucosal sites in the pharynx and sinuses, and 12 had abdominal or pelvic sites. Bacteremia was documented in 58% of patients, and operative debridement or drainage was required in 69%. The mortality rate was 24%. The classic features of necrotizing soft-tissue infections in these patients with streptococcal shock syndrome are often present, with organ system dysfunction out of proportion to the extent of local signs and symptoms and cutaneous necrosis occurring late. Conversely, a patient may present with marked cutaneous signs from deep tissue invasion after inadequate treatment or misdiagnosis of what began as a superficial infection. Prompt surgical intervention for streptococcal necrotizing soft-tissue infections is necessary, combined with antibiotic therapy. The infected muscle should be incised and adequately drained. If myonecrosis is present, it should be debrided. High-dose penicillin is bactericidal for this organism. Patients with a penicillin allergy should be administered erythromycin, tetracycline, or clindamycin. In a clinically septic patient or one with a Gram stain revealing a mixed infection, additional gramnegative coverage should be added to the penicillin.
598
SUTHERLAND & MEYER
The streptococcal toxic shock-like syndrome is extremely virulent. Death can occur within hours to days owing to refractory hypotension and respiratory failure. Although interest exists in the development of a vaccine against group A streptococci, at present little can be done to prevent the disease. Prompt recognition and appropriately aggressive therapy are required to reduce the mortality.
CLOSTRIDIAL INFECTIONS
Clostridia are obligate anaerobic, spore-forming bacilli. The organism can be found in soil, sewage, marine sediments, the gastrointestinal tract, and decaying animal and plant products. Of the 83 species of Clostridium, about one fourth can cause illness and infections in humans. 27 C. perfringens is responsible in the majority of trauma-related infections. IS C. septicum is more aerotolerant and is associated with spontaneous myonecrosis. Predisposing conditions include the presence of devitalized, inadequately debrided tissue following trauma-especially deep wounds, open fractures (perhaps compounded by constricting casts), and puncture wounds. Infection can also occur following colonic or biliary operations and has been reported following intramuscular injections, as alcohol does not kill the spores. 33 The association with malignant disease (especially gastrointestinal neoplasm) has been well documented/' 13, 42, 60 as there appears to be an increased incidence of both C. septicum bacteremia and the development of spontaneous myonecrosis. MacLennan43 separated the histotoxic clostridial infections into three forms: simple contamination, anaerobic cellulitis, and myonecrosis (gas gangrene). When clostridia are found in an untidy wound simply as a contaminant, other bacteria can usually be isolated, and there is no evidence of tissue invasion, only colonization. Treatment requires nothing more than debridement and local wound care. If debridement is delayed or inadequate, the spores germinate in an anaerobic environment. Several types of exotoxins are produced by clostridia, which account for their pathogenicity; particularly a-toxin, a lethininase that causes hemolysis, tissue liquefaction, and increased capillary permeability. Depending upon the strain, other toxins are produced that further advance the infection and account for the systemic signs and symptoms. The organism can cause an anaerobic cellulitis characterized by a foul discharge and possibly crepitance. Unlike the most severe form of infection, there is little or no pain, edema, or toxemia. It is necessary to inspect the underlying fascia and muscle at the time of debridement to exclude myonecrosis. The hallmark of deep tissue infection (myonecrosis) is intense pain out of proportion to the appearance of the wound. There may be mild swelling with a thin, nonpurulent, sickly sweet smelling discharge. Clostridia tend to exhibit variable morphology on Gram staining. Classically one sees large gram-positive rods with blunt ends, resembling "boxcars." Leukocytes are noticeably absent on Gram stain. With myo-
NECROTIZING SOFT-TISSUE INFECTIONS
599
necrosis, the signs of systemic toxicity are of rapid onset. The presence of crepitance on examination, hemorrhagic bullae, or tissue emphysema on radiography is a late sign. At the time of operation, the muscle involved is visibly edematous and pallid and fails to contract upon stimulation. If the process is advanced, the muscle is blackened and obviously necrotic. Muscular involvement can be extensive, extending beyond the limits of dermal involvement. Radical debridement is necessary owing to the aggressive nature of the organism. The incidence of amputation is very high, noted by Bakker2 to be 24.3% in his series of 230 patients with clostridial infection involving an extremity. Given the high mortality rate associated with this infection, early amputation of the extremity may be lifesaving. High-dose penicillin should be administered; clindamycin or metronidazole is substituted for patients with penicillin allergy. Plans should be made to re-explore the wound and debride as necessary within the next 12 to 24 hours. Hyperbaric oxygenation (HBO) can be considered, as it is bacteriostatic to the organism itself and appears to hinder the production of some exotoxins.62 However, it is important to stress surgical intervention as primary treatment, as both in vitro and in vivo studies reveal an insignificant effect by HBO in the presence of blood and necrotic tissue. 28,29 Kornbluth et a142 reviewed 162 cases of C. septicum infection and found an association with malignancy in 81%. In light of this finding, a search for an occult malignancy should be performed in patients who survive spontaneous myonecrosis with isolation of this organism.
INFECTIONS OF THE PERINEUM
Although the origin is occasionally idiopathic, the majority of necrotizing perineal soft-tissue infections can be determined to be of urogenital, anorectal, or dermal origin with proper evaluation. Clayton and associates lO reported a series of 57 patients with necrotizing fasciitis of the genitalia and found the origin to be urogenital in 45%, anorectal in 33%, and dermal in 21%. The initiating pathologic conditions include traumatic rectal perforations, perirectal abscess, posthemorrhoidectomy infection, pilonidal cyst, chronic prostatitis, epididymo-orchitis, periurethritis following instrumentation of the lower urinary tract, and surgery for hypospadias, circumcision, or penile prosthesis. Infection has also occurred after injections into the dorsal vein of the penis. In females the infection may follow a gynecologic procedure or an inadequately treated Bartholin's cyst abscess. Most patients with perineal necrotizing soft-tissue infections have an underlying systemic disease (diabetes mellitus) or are in a debilitated state of health from alcoholism or cancer. It has also been noted that patients wait an average of 5 days after the onset of symptoms before seeking medical advice3 so that what begins as a discomfort progresses to pain and not uncommonly results in systemic signs of sepsis. The only
600
SUTHERLAND & MEYER
clue to an infectious process may be the presence of dermal gangrene of the scrotum, as the subcutaneous tissue is relatively sparse in this region. Begley and co-workers5 have suggested the use of scrotal ultrasonography for early diagnosis in the few patients who present early, without obvious clinical signs. In the operating room the patient with possible perineal necrotizing soft-tissue infection is placed in the lithotomy position for access to all perineal structures. Proctoscopy and/or a retrograde urethrogram may be helpful in determining the cause and extent of the disease process. Incision of the perineum often reveals a purulent, malodorous fluid collection. The process extends into the adjacent adipose tissue, resulting in a patchy greenish black liquefaction necrosis from a mixed facultativeanaerobic infection. Radical debridement of all necrotic tissue is necessary, with preservation of the anal sphincter musculature if viable. Drains may be needed for the deep perirectal space to allow adequate drainage. For infections extending upward into the pelvis, a counterincision on the lower abdominal wall should be considered. Staying extraperitoneal, a communication can be made with the fascial plane to allow through-and-through irrigation. Repeat wound exploration should be performed within 12 to 24 hours after the initial debridement to evaluate for extension of the infection and debride as necessary. If the wound is clean, this serves as a time for dressing change. A suprapubic cystostomy is unnecessary if a urethral catheter is in place. It should be considered for the patient with urethral disruption or stricture. Likewise, a colostomy with distal washout should be performed if the sphincters are involved or a rectal perforation is present or to divert the fecal stream to reduce soiling of the open perineal wound. Orchiectomy is seldom required, as the blood supply to the testicles differs from that to the scrotum and penis. Wound culture usually reveals a polymicrobial infection/' 3 most commonly isolating Bacteroides, coliforms, Klebsiella, Proteus, Streptococcus, Staphylococcus, and Peptostreptococcus. These organisms interact in a synergistic fashion to produce a more destructive infectious process. Triple antibiotic therapy directed against gram-positive and gram-negative aerobes as well as anaerobes is begun preoperatively. Dressing changes should be performed with adequate analgesia. The majority of patients require skin grafting once the infection has resolved. If the scrotum has been excised, leaving the testicles exposed, they can be placed within a subcutaneous pouch in the medial thigh or lower abdominal wall. Another option is to return them to a position below the penis, use superficial sutures to join them together, and skin graft over the reconstructed scrotum at that time. Prior to colostomy closure, sphincter function must be assessed and repaired if feasible. In comparing perineal infections of urogenital versus anorectal origin, Enriquez et aP7 found that those of anorectal origin are diagnosed later in their course and, hence, are associated with deeper extension, more tissue destruction, and increased incidence of myonecrosis, all of which correlate with a higher mortality rate.
NECROTIZING SOFT-TISSUE INFECTIONS
601
EXTREMITY SEPSIS
Few necrotizing soft-tissue infections of the extremities require amputation. Most require only debridement and possibly skin grafting at a future date. As in other such infections, daily operative debridement is necessary until further necrosis is halted and systemic infectious symptoms resolve. A decision to amputate for necrotizing soft-tissue infections of an extremity should be based on the extent and progression of the infection, the original injury, and the vascular status of the limb in conjunction with the functional prospects and the overall condition of the patient. Not infrequently amputation may be necessary when the limb is deemed not salvageable or the infectious process progresses to a lifethreatening condition. The timing of this procedure can be critical. When dealing with the septic extremity, a two-stage procedure is recommended. 44 This involves a guillotine amputation followed in 3 to 7 days by a formal operation. In this manner, the incidence of wound complications, which often require revision to a higher amputation site, is reduced. Not only is the septic process isolated from systemic circulation, but a grossly contaminated wound is transformed to a clean contaminated wound. This allows primary closure of the wound at the second operation and has been shown to reduce the duration of hospitalization. 21 The relatively young, otherwise healthy patient can tolerate a second anesthetic with rare mortality. However, the elderly patient with acute metabolic derangements superimposed on chronic disease states faces a mortality rate up to 25% when an amputation is performed emergently in the face of sepsis. 32 The mortality rate for a second procedure following guillotine amputation in this population may also be significant. Physiologic cryoamputation has been advocated as a means to isolate the septic extremity and thereby defer an emergent operation in an elderly debilitated patient. Several methods have been described?' 8, 34, 61 Some favor the use of tourniquets placed just above the infectious process. Some also place a warming unit above this area, and either Dry Ice or a refrigerating device is placed on the distal extremity continuously. Cryoamputation usually halts the spread of infection and provides pain relief. The patient can then be resuscitated. Invasive monitors may be placed, and arrhythmias, congestive heart failure, pulmonary failure, renal failure, and diabetic ketoacidosis can be treated if present. With improved hemodynamic status, an emergent operation is converted to an elective operation, usually performed 48 to 72 hours later. This may translate into a reduced mortality, with rates of less than 15%.1,8,34 BuntB reported a mortality rate of 5.1 % for amputations performed after physiologic cryoamputation in an elderly, debilitated subset of patients who presented with pedal sepsis. Brinker et aF compared two groups of patients. The healthier (group I) patients had emergency surgery, and the sicker (group II) patients had cryoanesthesia followed by surgery. The mortality was similar in the two groups, 8% and 9%, respectively. Both groups displayed minimal morbidity. Of note, the average length
602
SUTHERLAND & MEYER
of hospital stay was 17.7 days for group II compared with 24.2 days for group I. HYPERBARIC OXYGENATION
Much has been written about the efficacy of HBO in the treatment of necrotizing soft-tissue infections, but its efficacy remains unproven. 26, 57, 58 Although some evidence suggests a beneficial effect of HBO from both animal studies and clinical reports, no controlled, randomized, prospective clinical trial has been done to date, Therefore, the precise benefit derived or the subgroup of patients best served remains ill defined. Undoubtedly, the diverse patient population and varied clinical course make it difficult to prove benefit, as revealed by improved outcome, from this treatment modality, Several mechanisms are postulated by which HBO may assist in control of both the infectious process and wound healing. 1, HBO increases the oxygen tension in the tissue bordering the
2,
3.
4.
5.
6.
infection, which is made ischemic by the inflammatory response and various bacterial toxins. 2 Leukocytes are activated and oxygen can be used as a substrate to produce an increased concentration of oxygen free radicals necessary to kill the phagocytosed microbes. 23 The increased oxygen tension may have a direct antimicrobial effect by decreasing the multiplication of anaerobes. 2 The production of endotoxin released by certain clostridial species may be diminished by HBO.29,62 Vasoconstriction is induced, reducing the reflex vasodilatation caused by the hypoxic inflammatory state. This may result in a decrease in the tissue edema, which could enhance the host's ability to fight the infection,48 Capillary angiogenesis is enhanced, as is fibroblast proliferation, which may lead to more rapid granulation tissue and wound healing,40
Potential complications of HBO should be kept in mind. 26 Barotrauma can aggravate sinusitis or cause tympanic membrane rupture, pneumothorax, or air embolism. Oxygen toxicity can affect both the pulmonary system and the central nervous system. Reversible visual changes can also occur. If a patient is hemodynamically unstable, an HBO chamber makes resuscitation difficult. HBO treatments are most dangerous in the critically ill patients at greatest risk of death from their infection. Furthermore, the use of HBO is limited by the patient's claustrophobia. Animal studies have been performed using intramuscular injection of clostridia. 16,29,31,38 They have shown a distinct advantage of HBO when used early, showing diminished tissue loss and decreased mortality rates. There was less of an advantage when used after 18 hours or without antibiotics or surgical intervention.
NECROTIZING SOFT-TISSUE INFECTIONS
603
Riseman et al57 reported a retrospective study evaluating 29 patients with necrotizing fasciitis over an 8-year period. Twelve patients received surgical debridement and antibiotics, and 17 received adjunctive HBO in addition to surgery and antibiotics. Epidemiology of the two groups as well as the wound bacteriology and antibiotic regimen was similar. The group receiving HBO appeared sicker, as 29% were in shock compared with 8% in the control group. They also had more perineal involvement-53% versus 12%-and 47% were diabetic, as opposed to 33% of the control group. Despite this, the HBO group required an average of 1.2 debridements and had a mortality rate of 23%. The control group required an average of 3.3 debridements, with a mortality rate of 66%. This study, however, was neither prospective nor randomized. Until objective evidence of benefit of HBO in prospective randomized trials is available, the use of HBO for necrotizing soft-tissue infections must be considered only potentially useful.
VARIANT FORMS OF NECROTIZING SOFT-TISSUE INFECTIONS
Infections involving the abdominal wall, lower chest, and/ or upper thigh should raise suspicion of an intra-abdominal process. This may be the initial manifestation of appendicitis, diverticulitis, or an occult malignancy with perforation into the retroperitoneum. As previously alluded to, this process can occur following elective procedures, especially when the bowel or biliary tract has been opened. Debridement often results in large fascial defects requiring the placement of mesh and/ or split-thickness skin grafts. Necrotizing infections of the head and neck are rare, probably owing to the robust regional blood supply. Overholt et al49 reported three cases and reviewed 18 previously reported cases of necrotizing infection of the eyelids. Group A l3-hemolytic streptococcus by itself or in combination with Staphylococcus aureus was isolated in every case. Some form of local trauma was identified in 72%; in 28%, the infection developed spontaneously. Half of the patients had an associated disease process (diabetes mellitus, alcoholism, or other); 72% were female. Although significant morbidity was noted, mortality was relatively low. Radical debridement is necessary, with a principal goal of saving the patient and a secondary goal of subsequent reconstruction. Cervical necrotizing soft-tissue infections are usually mixed infections of odontogenic origin. 54 When the infection occurs 1 to 2 weeks following a pharyngeal infection, it has been termed postanginal sepsis or Lemierre syndrome.9 Radical debridement, proper dental therapy, and broad-spectrum antibiotics are required. The mortality rate increases significantly with extension of the infectious process into the thorax. Marine Vibrio species have also been known to cause fulminant softtissue infection. 2o,53 Vibrio, a halophytic gram-negative bacillus, can cause three clinical syndromes-septicemia, gastroenteritis, and soft-tissue in-
604
SUTHERLAND & MEYER
fection. 41 Most patients are immunocompromised. Particular risk factors include liver disease, elevated serum iron levels, and low gastric acidity. Vibrio vulnificus is the most common organism identified. Gastroenteritis and/ or septicemia may follow the ingestion of raw oysters. Soft-tissue infections usually occur with exposure of an existing wound to seawater or if the patient sustains a wound while cleaning shellfish. Bullous skin lesions can develop as a result of septicemia. Typically, a fulminant cellulitis develops with secondary deep tissue invasion. Treatment requires aggressive wound debridement and antibiotics. Erythromycin is the drug of choice. Gentamicin or chloramphenicol is sometimes added. Opportunistic fungal infections are seen with increased frequency in severely debilitated patients and patients immunosuppressed because of transplantation or cancer therapy.47,51 Invasive phycomycotic fungal infections are known complications of diabetes mellitus, cancer, long-term antibiotic administration, and immunosuppression. Phycomycotic wound infections are rapidly invasive, grow deeply into tissues, and can become widely disseminated. Wide debridement is necessary in conjunction with intravenous amphotericin B. The use of fluconazole in invasive fungal infections as an alternative to amphotericin B remains unproven. The mortality rate was 80% in the report by Patino et aI.Sl
MORTALITY
Uncontrolled necrotizing soft-tissue infections progress to extensive tissue necrosis and florid sepsis leading to multisystem organ failure and/ or death. The overall mortality rate has been reported to be near 38%.1,35 Factors associated with increased mortality include age, truncal involvement, diabetes mellitus, and delay in diagnosis and/ or treatment. Rea and Wyrick 56 reported a mortality rate of 67% in patients more than 50 years of age, compared with 4% for those less than 50. Extremity infections are associated with lower mortality. Undoubtedly, the option of amputation allows for resolution of the infectious process when confined to the extremity, accounting for some of the decrease in mortality. Failure to control the infection at the time of the first operation increases the mortality rate from 43% to 71%.25 Pes sa and HowardS3 proposed the use of Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) and Surgical Infection Stratification scores as prognostic indicators, noting that death occurred in all patients whose scores increased from the third to seventh day following debridement. Further deterioration in patients with necrotizing soft-tissue infection after initial debridement is usually associated with incomplete surgical treatment or development of sepsis and sepsis syndrome. This also reflects the high mortality rate associated with the state of septic shock, accompanied by the high incidence of complications such as ARDS and acute renal failure.
NECROTIZING SOFT-TISSUE INFECTIONS
605
SUMMARY
In the realm of clinical practice, this disease entity defies applicability to any classification scheme. Of paramount importance is the early identification of all necrotizing soft-tissue infections. This requires a high index of suspicion, aided by recognition of various risk factors and organ system dysfunction out of proportion to the extent of local signs and symptoms. Expedient, aggressive surgical therapy is imperative: resuscitation, wide debridement, and antibiotic therapy. Once the infection has been controlled, continued supportive care, reconstruction, and rehabilitation can proceed. References 1. Ahrenholz DH: Necrotizing soft-tissue infections. Surg Clin North Am 68:199-214,1988 2. Bakker DJ: Clostridial myonecrosis. In Davis Je, Hunt TK (eds): Problem Wounds. The Role of Oxygen. New York, Elsevier, 1988, p 153 3. Baskin LS, Carroll PR, Cottolica EV, et al: Necrotizing soft tissue infections of the perineum and genitalia: Bacteriology, treatment, and risk assessment. Br J Urol 65:524, 1990 4. Baxter CR: Surgical management of soft tissue infections. Surg Clin North Am 52:1483, 1972 5. Begley MG, Shawker TH, Robertson CN, et al: Fournier's gangrene: DiagnOSis with scrotal ultrasound. Radiology 169:387, 1988 6. Bretzke ML, Bubrick MP, Hitchcock CR: Diffuse spreading Clostridium septicum infection, malignant disease and immune suppression. Surg Gynecol Obstet 166:197, 1988 7. Brinker MR, Timberlake GA, Goff JM, et al: Below-knee physiologic cryoanesthesia in the critically ill patient. J Vasc Surg 7:433,1988 8. Bunt TJ: Physiologic amputation for acute pedal sepsis. Am Surg 56:530, 1990 9. Chowdhury K, Bloom J, Black MJ, et al: Spontaneous and non-spontaneous internal jugular vein thrombosis. Head Neck 9:168,1990 10. Clayton MD, Fowler JE Jr, Sharifi R: Causes, presentation, and survival of 57 patients with necrotizing fasciitis of the male genitalia. Surg Gynecol Obstet 170:49, 1990 11. Cleary PP, Kaplan EL, Handley JP, et al: Clonal basis for resurgence of serious Streptococcus pyogenes disease in the 1980's. Lancet 339:518,1992 12. Cone LA, Woodard DR, Schlievert PM, et al: Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N Engl J Med 317:146,1987 13. Corey EC: Nontraumatic gas gangrene: Case report and review of emergency therapeutics. J Emerg Med 9:431, 1991 14. Davison AJ, Rotstein OD: The diagnosis and management of common soft-tissue infections. Can J Surg 31:333, 1988 15. Dellinger EP: Severe necrotizing soft-tissue infections. JAMA 246:15-17,1981 16. DeMello FT, Haglin H, Hitchcock CR: Comparative study of experimental Clostridium perfringens infection in dogs treated with antibiotics, surgery, and hyperbaric oxygen. Surgery 73:936, 1973 17. Enriquez JM, Moreno S, Devesa M, et al: Fournier's syndrome of urogenital and anorectal origin. Dis Colon Rectum 30:33, 1987 18. Falcone PA, Pricolo VE, Edstrom LE: Necrotizing fasciitis as a complication of chickenpox. Clin Pediatr 27:339, 1988 19. Ferrieri P, Kaplan EL, Handley JP: Invasive group A streptococcal infections. Infect Dis Clin North Am 6:149, 1992 20. File TM, Tan JS: Treatment of bacterial skin and soft tissue infections. Surg Gynecol Obstet 172:17, 1991 21. Fisher DF, Clagett GP, Fry RE: One-stage versus two-stage amputation for wet gangrene of the lower extremity: A randomized study. J Vasc Surg 8:428, 1988
606
SUTHERLAND & MEYER
22. Fisher JR, Conway MJ, Takeshita RT, et al: Necrotizing fasciitis: Importance of roentgenographic studies for soft-tissue gas. JAMA 241:803,1979 23. Forman HJ, Thomas MJ: Oxidant production and bactericidal activity of phagocytes. Annu Rev PhysioI48:669, 1986 24. Fournier FA: Etude clinique de la gangrene foudroyante de la verge. La Semaine Medicale 4:69,1884 25. Freischlag JA, Ajalat G, Busuttil RW: Treatment of necrotizing soft tissue infections: The need for a new approach. Am J Surg 149:751, 1985 26. Grim PS, Gottlieb LJ, Boddie A, et al: Hyperbaric oxygen therapy. JAMA 263:2216,1990 27. Hatheway CL: Toxigenic clostridia. Clin Microbiol Rev 3:66,1990 28. Hill GB, Osterhout S: Experimental effects of hyperbaric oxygen on selected clostridial species: 1. In-vitro studies. J Infect Dis 125:17, 1972 29. Hill GB, Osterhout S: Experimental effects of hyperbaric oxygen on selected clostridial species: II: In vivo studies in mice. J Infect Dis 125:26, 1972 30. Hitchcock CR: Overwhelming infections in trauma. Postgrad Med 82:77,1987 31. Holland JA, Hill GB, Wolfe WG, et al: Experimental and clinical experience with hyperbaric oxygen in the treatment of clostridial myonecrosis. Surgery 77:75, 1975 32. Holstedt GE, Bell JW: Sepsis and survival after above knee amputation for peripheral vascular disease. Am J Surg 103:371, 1962 33. Hullagan LF, Scott JL, Horowitz HC: Clostridial myonecrosis resulting from subcutaneous epinephrine suspension injection. Ann Emerg Med 21:434,1992 34. Hunsaker RH, Schwartz JA, Keagy BA, et al: Dry Ice cryoamputation: A twelve year experience. J Vasc Surg 2:812, 1985 35. Janevicius RV, Hann S, Butt MD: Necrotizing fasciitis. Surg Gynecol Obstet 154:97,1982 36. Jones J: Investigation upon the nature, causes and treatment of hospital gangrene as it prevailed in the confederate armies 1861-1865. In Hamilton FH (ed): Surgical Memoirs of the War of the Rebellion, US Sanitary Commission. New York, Riverside Press, 1871 37. Kaiser RE, Cerra FB: Progressive necrotizing surgical infections-a unified approach. J Trauma 21:349, 981 38. Kelley HG, Pace WG: Treatment of anaerobic infections in mice with hyperpressure oxygen. Surg Forum 14:46, 1963 39. Kingston 0, Seal DV: Current hypotheses on synergistic microbial gangrene. Br J Surg 77:260, 1990 40. Knighton DR, Silver JA, Hunt TK: Regulation of wound healing angiogenesis: Effect of oxygen gradients and improved oxygen concentration. Surgery 89:262, 1981 41. Koenig KL, Mueller J, Rose T: Vibrio vulniftcus: Hazard on the half shell. West J Med 155:400,1991 42. Kornbluth AA, Danzig JB, Bernstein LH: Clostridium septicum infection and associated malignancy. Medicine 68:30,1989 43. MacLennan JD: The histotoxic clostridial infection in man. Bacteriol Rev 26:177, 1962 44. McIntyre KE, Bailey SA, Malone JM, et al: Guillotine amputation in the treatment of non-salvageable lower extremity infections. Arch Surg 119:450, 1984 45. Meleney FL: A differential diagnosis between certain types of infectious gangrene of the skin-with particular reference to hemolytic streptococcus gangrene and bacterial synergistic gangrene. Surg Gynecol Obstet 56:847,1933 46. Meleney FL: Hemolytic streptococcus gangrene. Arch Surg 9:317, 1924 47. Newton WD, Cramer FS, Norwood SH: Necrotizing fasciitis from invasive phycomycetes. Clin Chest Med 15:331, 1987 48. Nylander G, Lewis 0, Nordstrom H, et al: Reduction of postischemic edema with hyperbaric oxygen. Plast Reconstr Surg 76:596, 1985 49. Overholt EM, Flint PW, Overholt EL, et al: Necrotizing fasciitis of the eyelids. Otolaryngol Head Neck Surg 106:339,1992 50. Patino JF, Castro 0: Necrotizing lesions of soft tissues: A review. World J Surg 15:235, 1991 51. Patino JF, Castro 0, Valenera A, et al: Necrotizing soft tissue lesions after a volcanic cataclysm. World J Surg 15:240, 1991 52. Paty R, Smith AD: Gangrene and Fournier's gangrene. Urol Clin North Am 19:149, 1992 53. Pessa ME, Howard RJ: Necrotizing fasciitis. Surg Gynecol Obstet 161:357,1985
NECROTIZING SOFT-TISSUE INFECTIONS
607
54. Rapport Y, Himelfarb MZ, Zikk D, et al: Cervical necrotizing fasciitis of odontogenic origin. Oral Surg Oral Med Oral Pathol 72:15, 1991 55. Ray D, Cohle SD, Lamb P: Spontaneous clostridial myonecrosis. J Forensic Sci 37:1428, 1992 56. Rea WI, Wyrick WJ: Necrotizing fasciitis. Am Surg 172:957, 1970 57. Riseman JA, Zamboni WA, Ross DO: Hyperbaric oxygen therapy reduces mortality and the need for debridement. Surgery 108:847, 1990 58. Rudge FW: The role of hyperbaric oxygenation in the treatment of clostridial myonecrosis. Milit Med 158:80, 1993 59. Stamenkovic I, Lew PD: Early recognition of potentially fatal necrotizing fasciitis: The role of frozen section biopsy. N Engl J Med 310:1689, 1984 60. Stevens DL: Musher DM, Watson DA, et al: Spontaneous, nontraumatic gangrene due to Clostridium septicum. Rev Infect Dis 12:286, 1990 61. Still HM, Wray CH, Moretz WH: Selected physiologic amputation: A valuable adjunct in preparation for surgical operation. Ann Surg 171:143, 1970 62. Van Unnik AJM: Inhibition of toxin production in Clostridum perfringes in vitro by hyperbaric oxygen. Antonie Van Leeuwenhoek 31:181,1965 63. Willoughby R, Grenberg RN: The toxic shock syndrome and streptococcal pyrogenic exotoxins. Ann Intern Med 98:559, 1983 64. Wilson B: Necrotizing fasciitis. Am Surg 172:957, 1970 65. Wood TF, Potter MA, Jonasson 0: Streptococcal toxic shock-like syndrome: The importance of surgical intervention. Ann Surg 217:109, 1993
Address reprint requests to Anthony A. Meyer, MD, PhD Department of Surgery University of North Carolina 164 Burnett Womack Campus Box 7210 Chapel Hill, NC 27599-7210
0039-6109/94 $0.00 + .20
NECROTIZING SOFT-TISSUE INFECTIONS Mark E. Sutherland, MO, and Anthony A. Meyer, MO, PhD
Necrotizing soft-tissue infections continue to challenge the practicing surgeon. These infections represent a diverse disease process; the term itself encompasses a continuum ranging from simple pyodermas to life-threatening infections. They vary in regard to anatomic location, tissue level of involvement, predisposing conditions, and offending organism(s). These factors, together with contributing factors of the host, result in a variety of presentations and subsequently affect the clinical course and prognosis. Consequently, this has led to the use of a variety of terms in the literature. Historically, the entity was known as hospital gangrene36 during the US Civil War. A variant of the disease has become known as Fournier's gangrene, after a necrotizing infection of the perineum was described by Fournier in 1884.24 Many gangrenous infections of the skin and soft tissues were labeled Meleney's gangrene following Meleney's description of acute hemolytic streptococcal gangrene46 and the synergistic association of anaerobic streptococci and staphylococci.46 Wilson64 preferred the term necrotizing jasciitis, finding fascial necrosis to be the most consistent manifestation of the disease. Clearly the term gas gangrene has served more to confuse than to clarify. Although this term was used initially to denote deep clostridial infections, the majority of gas-producing infections are caused by nonclostridial organisms, and a number of noninfectious processes may be responsible for the development of subcutaneous emphysema. It stands to reason that classification based upon the organism or tissue level involved would add to the confusion, as this information is rarely available preoperatively. From the Department of Surgery, Tulane University Medical Center, New Orleans, Louisiana (MES); and the Department of Surgery, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina (AAM)
SURGICAL CLINICS OF NORTH AMERICA VOLUME 74· NUMBER 3· JUNE 1994
591
592
SUTHERLAND & MEYER
Conceivably, this confusion may result in delay in both proper diagnosis and appropriate treatment, a disconcerting thought when one realizes that a time-honored surgical dictum remains true for necrotizing soft-tissue infections-early diagnosis along with rapid and aggressive surgical intervention reduces the associated morbidity and mortality of the disease process. Recognizing this, Baxter4 separated the infections based on the need for and extent of surgical intervention required to control the infection and optimize patient outcome. This confused state of terminology has led to difficulties in understanding the disease process. The various factors and generalities of this disease process are reviewed, as well as specific characteristics of the more common and discrete entities included under the umbrella diagnosis of necrotizing soft-tissue infections. A conscious effort is made to avoid the haphazard use of nonstandardized terminology.
PRESENTATION AND DIAGNOSIS
A patient presenting in florid sepsis with obvious skin involvement requires more thought with regard to treatment than to diagnosis. Conversely, one who presents with minimal cutaneous manifestations of necrotizing soft-tissue infection requires a high index of suspicion in order to make an early diagnosis. This can be extremely difficult when the infection occurs spontaneously, without history of an antecedent event. Recognizing predisposing factors of the host may assist the clinician, as the majority of patients have at least one of several co-morbid conditions. This includes chronic disease states such as diabetes mellitus, peripheral vascular disease, and parenteral drug use. Diabetics have premature small vessel abnormalities that limit blood flow and delivery of oxygen, leukocytes, and antibiotics. They also have an inherent neutrophil dysfunction, manifested by impaired phagocytosis and chemotaxis. This can be compounded by the presence of a functional neuropathy such that the usual initial symptom-pain-is not experienced by the patient, allowing the infection to progress. Other underlying disease states may include alcoholism, malnutrition, and AIDS. The patient may also be immunocompromised by malignancy or the administration of chemotherapy, resulting in granulocytopenia. The steroid-dependent chronic obstructive pulmonary disease patient, as well as the transplant recipient, is also at risk. Patients who have suffered severe injury have an increased incidence of infection secondary to breaks in the skin barrier, the presence of a foreign body, devitalized tissue, or a fluid collection-especially blood. Tissue edema, secondary to disruption of normal lymphatic flow or venous drainage, can also increase the risk of infection. Although the clinical course of the infectious process is influenced by the above factors, it also depends upon the virulence of the microbe and size of the inoculum. Thus, a variety of presenting signs and symp-
NECROTIZING SOFT-TISSUE INFECTIONS
593
toms have been described.* The physician must be aware that necrotizing soft-tissue infections may complicate even the most minor elective procedure, emergency procedure, or traumatic injury. Deep tissues may be the initial focus of the infectious process, with secondary skin involvement. Conversely, the fascia and muscle may become involved with invasion of what began as a superficial infection. An apparent cellulitis that fails to respond to standard therapy-appropriate antibiotics, elevation, immobility-must raise suspicion of more extensive infection. Classically, necrotizing soft-tissue infections present initially with localized pain and a deceptively benign appearance. I, 4,15,37 Dermal involvement becomes apparent as the infectious process spreads along fascial planes. Local signs of deep tissue infection may include cyanosis or bronzing of the skin. An example of this bronzing is shown in Figure 1. Induration becomes evident and is one of the most constant physical findings, Crepitance is present when the infection includes a gas-producing organism. As the inflammatory process causes thrombosis of the perforating vessels to the skin, epidermolysis or dermal gangrene may be seen. Sensation of the overlying skin can vary from severe pain to paresthesias and even anesthesia. In the extremity, decreased range of motion eventually occurs. Concurrently, systemic manifestations of sepsis develop-altered mental status, tachycardia, tachypnea, leukocytosis, *References 1, 4, 14, 15, 20, 30, 37, 39, 50.
Figure 1. A 62-year-old man with a necrotizing infection of the left leg. Note the bronzing of the skin over the calf.
594
SUTHERLAND & MEYER
hyperglycemia, oliguria, fever/chills, and metabolic acidosis. Bacteremia is rare, identified in only 11% of patients in one series. 22 These signs and symptoms are summarized in Table l. Radiographic studies seldom offer additional information. Plain films may reveal air in the soft tissues,22 the presence of a foreign body, or osteomyelitis in the underlying bone. Although gas in the tissue is a nonspecific finding, its presence should alert the clinician to the possibility of severe infection. Ultrasound or CT scan may be helpful on occasion for some deep infections when they identify air or extensive soft-tissue edema (e.g., retroperitoneal infection from diverticulitis). Nuclear medicine scans such as indium or gallium scans require too much time to obtain results to be of significant value. Wilson64 recommends attempts to pass a probe or a finger through an incision or opening in the skin along the plane just above the deep fascia to assess the presence and extent of undermining, a manifestation of subcutaneous and fascial necrosis. He thought that this separation at the fascia was a pathognomonic feature of the disease process he termed necrotizing jasciitis. Whenever the diagnosis is considered, it is best to either confirm or exclude a deep tissue infection with direct visual examination of the underlying muscle and fascia. Stamenkovic and Lew 59 stated that they were able to diagnose the presence of necrotizing fasciitis within an average time of 21 hours after the onset of symptoms by the use of frozen tissue sections. However, clinical presentation, suspicion of the presence of a necrotizing softtissue infection, and operative exploration remain the best diagnostic maneuvers. Most surgeons who have experience with necrotizing softtissue infections can make the diagnosis more rapidly in the operating room.
GENERAL PRINCIPLES OF TREATMENT
Kaiser and Cerra,37 as well as Dellinger,15 have recognized necrotizing soft-tissue infections to be "variations of the same disease process" and suggest that they be managed by means of a unified approach, in which all soft-tissue infections are treated as potentially life-threatening emergencies. The first tier of management requires aggressive resuscitative measures, often assisted by invasive monitoring in the surgical ICU. While correction of the metabolic derangement is begun, all other organ systems are assessed and supportive measures instituted if necessary. Concomitantly, broad-spectrum antibiotics are administered, and the tetanus status is reviewed and updated as needed. Empiric antibiotic coverage typically entails penicillin-G (3 million units every 4 hours), an aminoglycoside or a third-generation cephalosporin, and possibly clindamycin or metronidazole for additional anaerobic coverage. The choice of penicillin-G reflects the 60% to 70% incidence of Group A f3-hemolytic streptococci in these wounds. The wound should be explored expeditiously in the operating room.
NECROTIZING SOFT-TISSUE INFECTIONS
595
Table 1. SIGNS AND SYMPTOMS OF NECROTIZING SOFT-TISSUE INFECTIONS Local signs Inflammation Pain Swelling Redness or bronzing Warmth Loss of function Induration Cutaneous blistering or necrosis Induration Crepitance Persistence or progression of inflammation despite appropriate therapy Systemic signs Obtundation Fever or hypothermia Leukocytosis or leukopenia Shock Multiple organ dysfunction or failure
Even if a patient remains in septic shock after resuscitation and antibiotics are begun, surgical debridement should not be delayed. In such situations, correction of the septic state does not occur until the infection is excised. Delay only worsens outcome. The incision is made directly over the area of skin involved or the most indurated region. The skin incision(s) should be parallel to the neurovascular bundles and carried down to fascia. The underlying muscle and fascia are inspected; all necrotic tissue is excised in all directions to healthy viable tissue. Debridement is considered adequate when finger dissection can no longer easily separate the subcutaneous fat from the fascia. One should be reluctant to leave overlying flaps of skin and subcutaneous tissue, as these may hinder proper evaluation of the wound postoperatively and thereby delay further debridement. When burrowing areas of necrotic fat are absent and necrotizing fasciitis has been excluded, the skin flaps may be preserved because tissue cellulitis resolves rapidly with proper treatment, leaving viable skin. Tissue and fluid specimens should be obtained from beneath intact skin, well away from any open wound. This should be sent for Gram stain as well as aerobic and anaerobic cultures with sensitivities. The wound is packed open and kept moist with saline. Antibiotic solutions have not been found to be necessary, and some stain the tissue and prevent inspection for necrosis. The patient should be returned to the operating room every 24 hours until progression of the necrosis is halted. Failure to re-explore the wound can lead to progression of the infection to previously healthy tissue, as seen in Figure 2. Further daily exploration under general anesthesia is especially recommended for truncal infections and for all patients who remain clinically septic. Postoperatively, these patients often require leu care so that cardiac, pulmonary, renal, and metabolic systems can be monitored and opti-
596
SUTHERLAND & MEYER
Figure 2. A 23-year-old man 3 days following debridement of a right antecubital infection without subsequent re-exploration. Note the progressive cellulitis and pitting edema on the chest wall.
mized. Choice of antibiotics is based on identification and sensitivity of the organism(s) isolated. Early enteral nutritional support is clearly beneficial in these patients. If this route is not tolerated, parenteral nutrition should be administered. Many patients benefit from a specialized bed to prevent skin breakdown. It is also helpful to institute physical and/or occupational therapy at an early stage once sepsis has resolved. Many authorities 1• 15 are reluctant to cover the site until they are assured that the infection is completely resolved. At that time, skin grafts are applied to granulation tissue, and free or rotational soft-tissue flaps are used to cover exposed bone, cartilage, tendons, and neurovascular structures. This should be done as soon as possible to preserve function and prevent wound problems.
STREPTOCOCCAL INFECTIONS
Group A streptococcus (Streptococcus pyogenes) can inflict disease in several organ systems, and infection of the soft tissues can occur at any leveP9 These organisms are the most common cause of necrotizing softtissue infection. The more benign forms include cellulitis, lymphangitis, and impetigo, and the more severe forms include erysipelas, necrotizing
NECROTIZING SOFT-TISSUE INFECTIONS
597
fasciitis, and streptococcal myositis. As previously stated, this latter entity was described as streptococcal gangrene by Meleney in 1924. 46 It has since acquired other names such as necrotizing erysipelas. Currently, a streptococcal toxic shock-like syndrome has evolved. 12 ,65 With an increase in the incidence of streptococcal infections being noted, it is feared that the organism may be acquiring greater virulence. l l Conditions that predispose to streptococcal infections include intravenous drug abuse, atherosclerotic vascular disease, and any immunocompromised state. Invasive streptococcal infection affects all ages from neonates to geriatric patients and can follow minor or major trauma. It has also been reported following a varicella infection. ls Perhaps the most alarming aspect of streptococcal infection is its ability to cause severe disease in otherwise healthy patients, whereas clostridial and mixed facultative-anaerobic infections have a predilection for debilitated hosts. The classification of the various strains of streptococci depends upon the type of M protein, a surface protein allowing the organism to adhere and colonize, the first step in gaining a foothold leading to invasion. It also helps the organism to evade phagocytosis by neutrophils in the absence of type-specific antibody. The pathogenicity is derived from the production of a variety of extracellular substances-cytotoxins, streptokinase, hemolysins, and pyrogenic exotoxins A, B, and C. The toxins may damage tissues by a direct effect upon the cells or indirectly by stimulation of the monocytes to produce an inflammatory response. The infection spreads along fascial planes and/ or through muscle groups. The streptococcal toxic shock-like syndrome was first postulated in 1983. 63 It consists of hypotension, fever, rash, desquamation, and multiorgan-system dysfunction. In reviewing the literature, Wood and co-workers65 found more than 50 reported cases. The patients' ages ranged from 14 months to 76 years, and the majority were female (68%). Although the leading sites of infection were the skin and soft tissues, 12 patients had mucosal sites in the pharynx and sinuses, and 12 had abdominal or pelvic sites. Bacteremia was documented in 58% of patients, and operative debridement or drainage was required in 69%. The mortality rate was 24%. The classic features of necrotizing soft-tissue infections in these patients with streptococcal shock syndrome are often present, with organ system dysfunction out of proportion to the extent of local signs and symptoms and cutaneous necrosis occurring late. Conversely, a patient may present with marked cutaneous signs from deep tissue invasion after inadequate treatment or misdiagnosis of what began as a superficial infection. Prompt surgical intervention for streptococcal necrotizing soft-tissue infections is necessary, combined with antibiotic therapy. The infected muscle should be incised and adequately drained. If myonecrosis is present, it should be debrided. High-dose penicillin is bactericidal for this organism. Patients with a penicillin allergy should be administered erythromycin, tetracycline, or clindamycin. In a clinically septic patient or one with a Gram stain revealing a mixed infection, additional gramnegative coverage should be added to the penicillin.
598
SUTHERLAND & MEYER
The streptococcal toxic shock-like syndrome is extremely virulent. Death can occur within hours to days owing to refractory hypotension and respiratory failure. Although interest exists in the development of a vaccine against group A streptococci, at present little can be done to prevent the disease. Prompt recognition and appropriately aggressive therapy are required to reduce the mortality.
CLOSTRIDIAL INFECTIONS
Clostridia are obligate anaerobic, spore-forming bacilli. The organism can be found in soil, sewage, marine sediments, the gastrointestinal tract, and decaying animal and plant products. Of the 83 species of Clostridium, about one fourth can cause illness and infections in humans. 27 C. perfringens is responsible in the majority of trauma-related infections. IS C. septicum is more aerotolerant and is associated with spontaneous myonecrosis. Predisposing conditions include the presence of devitalized, inadequately debrided tissue following trauma-especially deep wounds, open fractures (perhaps compounded by constricting casts), and puncture wounds. Infection can also occur following colonic or biliary operations and has been reported following intramuscular injections, as alcohol does not kill the spores. 33 The association with malignant disease (especially gastrointestinal neoplasm) has been well documented/' 13, 42, 60 as there appears to be an increased incidence of both C. septicum bacteremia and the development of spontaneous myonecrosis. MacLennan43 separated the histotoxic clostridial infections into three forms: simple contamination, anaerobic cellulitis, and myonecrosis (gas gangrene). When clostridia are found in an untidy wound simply as a contaminant, other bacteria can usually be isolated, and there is no evidence of tissue invasion, only colonization. Treatment requires nothing more than debridement and local wound care. If debridement is delayed or inadequate, the spores germinate in an anaerobic environment. Several types of exotoxins are produced by clostridia, which account for their pathogenicity; particularly a-toxin, a lethininase that causes hemolysis, tissue liquefaction, and increased capillary permeability. Depending upon the strain, other toxins are produced that further advance the infection and account for the systemic signs and symptoms. The organism can cause an anaerobic cellulitis characterized by a foul discharge and possibly crepitance. Unlike the most severe form of infection, there is little or no pain, edema, or toxemia. It is necessary to inspect the underlying fascia and muscle at the time of debridement to exclude myonecrosis. The hallmark of deep tissue infection (myonecrosis) is intense pain out of proportion to the appearance of the wound. There may be mild swelling with a thin, nonpurulent, sickly sweet smelling discharge. Clostridia tend to exhibit variable morphology on Gram staining. Classically one sees large gram-positive rods with blunt ends, resembling "boxcars." Leukocytes are noticeably absent on Gram stain. With myo-
NECROTIZING SOFT-TISSUE INFECTIONS
599
necrosis, the signs of systemic toxicity are of rapid onset. The presence of crepitance on examination, hemorrhagic bullae, or tissue emphysema on radiography is a late sign. At the time of operation, the muscle involved is visibly edematous and pallid and fails to contract upon stimulation. If the process is advanced, the muscle is blackened and obviously necrotic. Muscular involvement can be extensive, extending beyond the limits of dermal involvement. Radical debridement is necessary owing to the aggressive nature of the organism. The incidence of amputation is very high, noted by Bakker2 to be 24.3% in his series of 230 patients with clostridial infection involving an extremity. Given the high mortality rate associated with this infection, early amputation of the extremity may be lifesaving. High-dose penicillin should be administered; clindamycin or metronidazole is substituted for patients with penicillin allergy. Plans should be made to re-explore the wound and debride as necessary within the next 12 to 24 hours. Hyperbaric oxygenation (HBO) can be considered, as it is bacteriostatic to the organism itself and appears to hinder the production of some exotoxins.62 However, it is important to stress surgical intervention as primary treatment, as both in vitro and in vivo studies reveal an insignificant effect by HBO in the presence of blood and necrotic tissue. 28,29 Kornbluth et a142 reviewed 162 cases of C. septicum infection and found an association with malignancy in 81%. In light of this finding, a search for an occult malignancy should be performed in patients who survive spontaneous myonecrosis with isolation of this organism.
INFECTIONS OF THE PERINEUM
Although the origin is occasionally idiopathic, the majority of necrotizing perineal soft-tissue infections can be determined to be of urogenital, anorectal, or dermal origin with proper evaluation. Clayton and associates lO reported a series of 57 patients with necrotizing fasciitis of the genitalia and found the origin to be urogenital in 45%, anorectal in 33%, and dermal in 21%. The initiating pathologic conditions include traumatic rectal perforations, perirectal abscess, posthemorrhoidectomy infection, pilonidal cyst, chronic prostatitis, epididymo-orchitis, periurethritis following instrumentation of the lower urinary tract, and surgery for hypospadias, circumcision, or penile prosthesis. Infection has also occurred after injections into the dorsal vein of the penis. In females the infection may follow a gynecologic procedure or an inadequately treated Bartholin's cyst abscess. Most patients with perineal necrotizing soft-tissue infections have an underlying systemic disease (diabetes mellitus) or are in a debilitated state of health from alcoholism or cancer. It has also been noted that patients wait an average of 5 days after the onset of symptoms before seeking medical advice3 so that what begins as a discomfort progresses to pain and not uncommonly results in systemic signs of sepsis. The only
600
SUTHERLAND & MEYER
clue to an infectious process may be the presence of dermal gangrene of the scrotum, as the subcutaneous tissue is relatively sparse in this region. Begley and co-workers5 have suggested the use of scrotal ultrasonography for early diagnosis in the few patients who present early, without obvious clinical signs. In the operating room the patient with possible perineal necrotizing soft-tissue infection is placed in the lithotomy position for access to all perineal structures. Proctoscopy and/or a retrograde urethrogram may be helpful in determining the cause and extent of the disease process. Incision of the perineum often reveals a purulent, malodorous fluid collection. The process extends into the adjacent adipose tissue, resulting in a patchy greenish black liquefaction necrosis from a mixed facultativeanaerobic infection. Radical debridement of all necrotic tissue is necessary, with preservation of the anal sphincter musculature if viable. Drains may be needed for the deep perirectal space to allow adequate drainage. For infections extending upward into the pelvis, a counterincision on the lower abdominal wall should be considered. Staying extraperitoneal, a communication can be made with the fascial plane to allow through-and-through irrigation. Repeat wound exploration should be performed within 12 to 24 hours after the initial debridement to evaluate for extension of the infection and debride as necessary. If the wound is clean, this serves as a time for dressing change. A suprapubic cystostomy is unnecessary if a urethral catheter is in place. It should be considered for the patient with urethral disruption or stricture. Likewise, a colostomy with distal washout should be performed if the sphincters are involved or a rectal perforation is present or to divert the fecal stream to reduce soiling of the open perineal wound. Orchiectomy is seldom required, as the blood supply to the testicles differs from that to the scrotum and penis. Wound culture usually reveals a polymicrobial infection/' 3 most commonly isolating Bacteroides, coliforms, Klebsiella, Proteus, Streptococcus, Staphylococcus, and Peptostreptococcus. These organisms interact in a synergistic fashion to produce a more destructive infectious process. Triple antibiotic therapy directed against gram-positive and gram-negative aerobes as well as anaerobes is begun preoperatively. Dressing changes should be performed with adequate analgesia. The majority of patients require skin grafting once the infection has resolved. If the scrotum has been excised, leaving the testicles exposed, they can be placed within a subcutaneous pouch in the medial thigh or lower abdominal wall. Another option is to return them to a position below the penis, use superficial sutures to join them together, and skin graft over the reconstructed scrotum at that time. Prior to colostomy closure, sphincter function must be assessed and repaired if feasible. In comparing perineal infections of urogenital versus anorectal origin, Enriquez et aP7 found that those of anorectal origin are diagnosed later in their course and, hence, are associated with deeper extension, more tissue destruction, and increased incidence of myonecrosis, all of which correlate with a higher mortality rate.
NECROTIZING SOFT-TISSUE INFECTIONS
601
EXTREMITY SEPSIS
Few necrotizing soft-tissue infections of the extremities require amputation. Most require only debridement and possibly skin grafting at a future date. As in other such infections, daily operative debridement is necessary until further necrosis is halted and systemic infectious symptoms resolve. A decision to amputate for necrotizing soft-tissue infections of an extremity should be based on the extent and progression of the infection, the original injury, and the vascular status of the limb in conjunction with the functional prospects and the overall condition of the patient. Not infrequently amputation may be necessary when the limb is deemed not salvageable or the infectious process progresses to a lifethreatening condition. The timing of this procedure can be critical. When dealing with the septic extremity, a two-stage procedure is recommended. 44 This involves a guillotine amputation followed in 3 to 7 days by a formal operation. In this manner, the incidence of wound complications, which often require revision to a higher amputation site, is reduced. Not only is the septic process isolated from systemic circulation, but a grossly contaminated wound is transformed to a clean contaminated wound. This allows primary closure of the wound at the second operation and has been shown to reduce the duration of hospitalization. 21 The relatively young, otherwise healthy patient can tolerate a second anesthetic with rare mortality. However, the elderly patient with acute metabolic derangements superimposed on chronic disease states faces a mortality rate up to 25% when an amputation is performed emergently in the face of sepsis. 32 The mortality rate for a second procedure following guillotine amputation in this population may also be significant. Physiologic cryoamputation has been advocated as a means to isolate the septic extremity and thereby defer an emergent operation in an elderly debilitated patient. Several methods have been described?' 8, 34, 61 Some favor the use of tourniquets placed just above the infectious process. Some also place a warming unit above this area, and either Dry Ice or a refrigerating device is placed on the distal extremity continuously. Cryoamputation usually halts the spread of infection and provides pain relief. The patient can then be resuscitated. Invasive monitors may be placed, and arrhythmias, congestive heart failure, pulmonary failure, renal failure, and diabetic ketoacidosis can be treated if present. With improved hemodynamic status, an emergent operation is converted to an elective operation, usually performed 48 to 72 hours later. This may translate into a reduced mortality, with rates of less than 15%.1,8,34 BuntB reported a mortality rate of 5.1 % for amputations performed after physiologic cryoamputation in an elderly, debilitated subset of patients who presented with pedal sepsis. Brinker et aF compared two groups of patients. The healthier (group I) patients had emergency surgery, and the sicker (group II) patients had cryoanesthesia followed by surgery. The mortality was similar in the two groups, 8% and 9%, respectively. Both groups displayed minimal morbidity. Of note, the average length
602
SUTHERLAND & MEYER
of hospital stay was 17.7 days for group II compared with 24.2 days for group I. HYPERBARIC OXYGENATION
Much has been written about the efficacy of HBO in the treatment of necrotizing soft-tissue infections, but its efficacy remains unproven. 26, 57, 58 Although some evidence suggests a beneficial effect of HBO from both animal studies and clinical reports, no controlled, randomized, prospective clinical trial has been done to date, Therefore, the precise benefit derived or the subgroup of patients best served remains ill defined. Undoubtedly, the diverse patient population and varied clinical course make it difficult to prove benefit, as revealed by improved outcome, from this treatment modality, Several mechanisms are postulated by which HBO may assist in control of both the infectious process and wound healing. 1, HBO increases the oxygen tension in the tissue bordering the
2,
3.
4.
5.
6.
infection, which is made ischemic by the inflammatory response and various bacterial toxins. 2 Leukocytes are activated and oxygen can be used as a substrate to produce an increased concentration of oxygen free radicals necessary to kill the phagocytosed microbes. 23 The increased oxygen tension may have a direct antimicrobial effect by decreasing the multiplication of anaerobes. 2 The production of endotoxin released by certain clostridial species may be diminished by HBO.29,62 Vasoconstriction is induced, reducing the reflex vasodilatation caused by the hypoxic inflammatory state. This may result in a decrease in the tissue edema, which could enhance the host's ability to fight the infection,48 Capillary angiogenesis is enhanced, as is fibroblast proliferation, which may lead to more rapid granulation tissue and wound healing,40
Potential complications of HBO should be kept in mind. 26 Barotrauma can aggravate sinusitis or cause tympanic membrane rupture, pneumothorax, or air embolism. Oxygen toxicity can affect both the pulmonary system and the central nervous system. Reversible visual changes can also occur. If a patient is hemodynamically unstable, an HBO chamber makes resuscitation difficult. HBO treatments are most dangerous in the critically ill patients at greatest risk of death from their infection. Furthermore, the use of HBO is limited by the patient's claustrophobia. Animal studies have been performed using intramuscular injection of clostridia. 16,29,31,38 They have shown a distinct advantage of HBO when used early, showing diminished tissue loss and decreased mortality rates. There was less of an advantage when used after 18 hours or without antibiotics or surgical intervention.
NECROTIZING SOFT-TISSUE INFECTIONS
603
Riseman et al57 reported a retrospective study evaluating 29 patients with necrotizing fasciitis over an 8-year period. Twelve patients received surgical debridement and antibiotics, and 17 received adjunctive HBO in addition to surgery and antibiotics. Epidemiology of the two groups as well as the wound bacteriology and antibiotic regimen was similar. The group receiving HBO appeared sicker, as 29% were in shock compared with 8% in the control group. They also had more perineal involvement-53% versus 12%-and 47% were diabetic, as opposed to 33% of the control group. Despite this, the HBO group required an average of 1.2 debridements and had a mortality rate of 23%. The control group required an average of 3.3 debridements, with a mortality rate of 66%. This study, however, was neither prospective nor randomized. Until objective evidence of benefit of HBO in prospective randomized trials is available, the use of HBO for necrotizing soft-tissue infections must be considered only potentially useful.
VARIANT FORMS OF NECROTIZING SOFT-TISSUE INFECTIONS
Infections involving the abdominal wall, lower chest, and/ or upper thigh should raise suspicion of an intra-abdominal process. This may be the initial manifestation of appendicitis, diverticulitis, or an occult malignancy with perforation into the retroperitoneum. As previously alluded to, this process can occur following elective procedures, especially when the bowel or biliary tract has been opened. Debridement often results in large fascial defects requiring the placement of mesh and/ or split-thickness skin grafts. Necrotizing infections of the head and neck are rare, probably owing to the robust regional blood supply. Overholt et al49 reported three cases and reviewed 18 previously reported cases of necrotizing infection of the eyelids. Group A l3-hemolytic streptococcus by itself or in combination with Staphylococcus aureus was isolated in every case. Some form of local trauma was identified in 72%; in 28%, the infection developed spontaneously. Half of the patients had an associated disease process (diabetes mellitus, alcoholism, or other); 72% were female. Although significant morbidity was noted, mortality was relatively low. Radical debridement is necessary, with a principal goal of saving the patient and a secondary goal of subsequent reconstruction. Cervical necrotizing soft-tissue infections are usually mixed infections of odontogenic origin. 54 When the infection occurs 1 to 2 weeks following a pharyngeal infection, it has been termed postanginal sepsis or Lemierre syndrome.9 Radical debridement, proper dental therapy, and broad-spectrum antibiotics are required. The mortality rate increases significantly with extension of the infectious process into the thorax. Marine Vibrio species have also been known to cause fulminant softtissue infection. 2o,53 Vibrio, a halophytic gram-negative bacillus, can cause three clinical syndromes-septicemia, gastroenteritis, and soft-tissue in-
604
SUTHERLAND & MEYER
fection. 41 Most patients are immunocompromised. Particular risk factors include liver disease, elevated serum iron levels, and low gastric acidity. Vibrio vulnificus is the most common organism identified. Gastroenteritis and/ or septicemia may follow the ingestion of raw oysters. Soft-tissue infections usually occur with exposure of an existing wound to seawater or if the patient sustains a wound while cleaning shellfish. Bullous skin lesions can develop as a result of septicemia. Typically, a fulminant cellulitis develops with secondary deep tissue invasion. Treatment requires aggressive wound debridement and antibiotics. Erythromycin is the drug of choice. Gentamicin or chloramphenicol is sometimes added. Opportunistic fungal infections are seen with increased frequency in severely debilitated patients and patients immunosuppressed because of transplantation or cancer therapy.47,51 Invasive phycomycotic fungal infections are known complications of diabetes mellitus, cancer, long-term antibiotic administration, and immunosuppression. Phycomycotic wound infections are rapidly invasive, grow deeply into tissues, and can become widely disseminated. Wide debridement is necessary in conjunction with intravenous amphotericin B. The use of fluconazole in invasive fungal infections as an alternative to amphotericin B remains unproven. The mortality rate was 80% in the report by Patino et aI.Sl
MORTALITY
Uncontrolled necrotizing soft-tissue infections progress to extensive tissue necrosis and florid sepsis leading to multisystem organ failure and/ or death. The overall mortality rate has been reported to be near 38%.1,35 Factors associated with increased mortality include age, truncal involvement, diabetes mellitus, and delay in diagnosis and/ or treatment. Rea and Wyrick 56 reported a mortality rate of 67% in patients more than 50 years of age, compared with 4% for those less than 50. Extremity infections are associated with lower mortality. Undoubtedly, the option of amputation allows for resolution of the infectious process when confined to the extremity, accounting for some of the decrease in mortality. Failure to control the infection at the time of the first operation increases the mortality rate from 43% to 71%.25 Pes sa and HowardS3 proposed the use of Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) and Surgical Infection Stratification scores as prognostic indicators, noting that death occurred in all patients whose scores increased from the third to seventh day following debridement. Further deterioration in patients with necrotizing soft-tissue infection after initial debridement is usually associated with incomplete surgical treatment or development of sepsis and sepsis syndrome. This also reflects the high mortality rate associated with the state of septic shock, accompanied by the high incidence of complications such as ARDS and acute renal failure.
NECROTIZING SOFT-TISSUE INFECTIONS
605
SUMMARY
In the realm of clinical practice, this disease entity defies applicability to any classification scheme. Of paramount importance is the early identification of all necrotizing soft-tissue infections. This requires a high index of suspicion, aided by recognition of various risk factors and organ system dysfunction out of proportion to the extent of local signs and symptoms. Expedient, aggressive surgical therapy is imperative: resuscitation, wide debridement, and antibiotic therapy. Once the infection has been controlled, continued supportive care, reconstruction, and rehabilitation can proceed. References 1. Ahrenholz DH: Necrotizing soft-tissue infections. Surg Clin North Am 68:199-214,1988 2. Bakker DJ: Clostridial myonecrosis. In Davis Je, Hunt TK (eds): Problem Wounds. The Role of Oxygen. New York, Elsevier, 1988, p 153 3. Baskin LS, Carroll PR, Cottolica EV, et al: Necrotizing soft tissue infections of the perineum and genitalia: Bacteriology, treatment, and risk assessment. Br J Urol 65:524, 1990 4. Baxter CR: Surgical management of soft tissue infections. Surg Clin North Am 52:1483, 1972 5. Begley MG, Shawker TH, Robertson CN, et al: Fournier's gangrene: DiagnOSis with scrotal ultrasound. Radiology 169:387, 1988 6. Bretzke ML, Bubrick MP, Hitchcock CR: Diffuse spreading Clostridium septicum infection, malignant disease and immune suppression. Surg Gynecol Obstet 166:197, 1988 7. Brinker MR, Timberlake GA, Goff JM, et al: Below-knee physiologic cryoanesthesia in the critically ill patient. J Vasc Surg 7:433,1988 8. Bunt TJ: Physiologic amputation for acute pedal sepsis. Am Surg 56:530, 1990 9. Chowdhury K, Bloom J, Black MJ, et al: Spontaneous and non-spontaneous internal jugular vein thrombosis. Head Neck 9:168,1990 10. Clayton MD, Fowler JE Jr, Sharifi R: Causes, presentation, and survival of 57 patients with necrotizing fasciitis of the male genitalia. Surg Gynecol Obstet 170:49, 1990 11. Cleary PP, Kaplan EL, Handley JP, et al: Clonal basis for resurgence of serious Streptococcus pyogenes disease in the 1980's. Lancet 339:518,1992 12. Cone LA, Woodard DR, Schlievert PM, et al: Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N Engl J Med 317:146,1987 13. Corey EC: Nontraumatic gas gangrene: Case report and review of emergency therapeutics. J Emerg Med 9:431, 1991 14. Davison AJ, Rotstein OD: The diagnosis and management of common soft-tissue infections. Can J Surg 31:333, 1988 15. Dellinger EP: Severe necrotizing soft-tissue infections. JAMA 246:15-17,1981 16. DeMello FT, Haglin H, Hitchcock CR: Comparative study of experimental Clostridium perfringens infection in dogs treated with antibiotics, surgery, and hyperbaric oxygen. Surgery 73:936, 1973 17. Enriquez JM, Moreno S, Devesa M, et al: Fournier's syndrome of urogenital and anorectal origin. Dis Colon Rectum 30:33, 1987 18. Falcone PA, Pricolo VE, Edstrom LE: Necrotizing fasciitis as a complication of chickenpox. Clin Pediatr 27:339, 1988 19. Ferrieri P, Kaplan EL, Handley JP: Invasive group A streptococcal infections. Infect Dis Clin North Am 6:149, 1992 20. File TM, Tan JS: Treatment of bacterial skin and soft tissue infections. Surg Gynecol Obstet 172:17, 1991 21. Fisher DF, Clagett GP, Fry RE: One-stage versus two-stage amputation for wet gangrene of the lower extremity: A randomized study. J Vasc Surg 8:428, 1988
606
SUTHERLAND & MEYER
22. Fisher JR, Conway MJ, Takeshita RT, et al: Necrotizing fasciitis: Importance of roentgenographic studies for soft-tissue gas. JAMA 241:803,1979 23. Forman HJ, Thomas MJ: Oxidant production and bactericidal activity of phagocytes. Annu Rev PhysioI48:669, 1986 24. Fournier FA: Etude clinique de la gangrene foudroyante de la verge. La Semaine Medicale 4:69,1884 25. Freischlag JA, Ajalat G, Busuttil RW: Treatment of necrotizing soft tissue infections: The need for a new approach. Am J Surg 149:751, 1985 26. Grim PS, Gottlieb LJ, Boddie A, et al: Hyperbaric oxygen therapy. JAMA 263:2216,1990 27. Hatheway CL: Toxigenic clostridia. Clin Microbiol Rev 3:66,1990 28. Hill GB, Osterhout S: Experimental effects of hyperbaric oxygen on selected clostridial species: 1. In-vitro studies. J Infect Dis 125:17, 1972 29. Hill GB, Osterhout S: Experimental effects of hyperbaric oxygen on selected clostridial species: II: In vivo studies in mice. J Infect Dis 125:26, 1972 30. Hitchcock CR: Overwhelming infections in trauma. Postgrad Med 82:77,1987 31. Holland JA, Hill GB, Wolfe WG, et al: Experimental and clinical experience with hyperbaric oxygen in the treatment of clostridial myonecrosis. Surgery 77:75, 1975 32. Holstedt GE, Bell JW: Sepsis and survival after above knee amputation for peripheral vascular disease. Am J Surg 103:371, 1962 33. Hullagan LF, Scott JL, Horowitz HC: Clostridial myonecrosis resulting from subcutaneous epinephrine suspension injection. Ann Emerg Med 21:434,1992 34. Hunsaker RH, Schwartz JA, Keagy BA, et al: Dry Ice cryoamputation: A twelve year experience. J Vasc Surg 2:812, 1985 35. Janevicius RV, Hann S, Butt MD: Necrotizing fasciitis. Surg Gynecol Obstet 154:97,1982 36. Jones J: Investigation upon the nature, causes and treatment of hospital gangrene as it prevailed in the confederate armies 1861-1865. In Hamilton FH (ed): Surgical Memoirs of the War of the Rebellion, US Sanitary Commission. New York, Riverside Press, 1871 37. Kaiser RE, Cerra FB: Progressive necrotizing surgical infections-a unified approach. J Trauma 21:349, 981 38. Kelley HG, Pace WG: Treatment of anaerobic infections in mice with hyperpressure oxygen. Surg Forum 14:46, 1963 39. Kingston 0, Seal DV: Current hypotheses on synergistic microbial gangrene. Br J Surg 77:260, 1990 40. Knighton DR, Silver JA, Hunt TK: Regulation of wound healing angiogenesis: Effect of oxygen gradients and improved oxygen concentration. Surgery 89:262, 1981 41. Koenig KL, Mueller J, Rose T: Vibrio vulniftcus: Hazard on the half shell. West J Med 155:400,1991 42. Kornbluth AA, Danzig JB, Bernstein LH: Clostridium septicum infection and associated malignancy. Medicine 68:30,1989 43. MacLennan JD: The histotoxic clostridial infection in man. Bacteriol Rev 26:177, 1962 44. McIntyre KE, Bailey SA, Malone JM, et al: Guillotine amputation in the treatment of non-salvageable lower extremity infections. Arch Surg 119:450, 1984 45. Meleney FL: A differential diagnosis between certain types of infectious gangrene of the skin-with particular reference to hemolytic streptococcus gangrene and bacterial synergistic gangrene. Surg Gynecol Obstet 56:847,1933 46. Meleney FL: Hemolytic streptococcus gangrene. Arch Surg 9:317, 1924 47. Newton WD, Cramer FS, Norwood SH: Necrotizing fasciitis from invasive phycomycetes. Clin Chest Med 15:331, 1987 48. Nylander G, Lewis 0, Nordstrom H, et al: Reduction of postischemic edema with hyperbaric oxygen. Plast Reconstr Surg 76:596, 1985 49. Overholt EM, Flint PW, Overholt EL, et al: Necrotizing fasciitis of the eyelids. Otolaryngol Head Neck Surg 106:339,1992 50. Patino JF, Castro 0: Necrotizing lesions of soft tissues: A review. World J Surg 15:235, 1991 51. Patino JF, Castro 0, Valenera A, et al: Necrotizing soft tissue lesions after a volcanic cataclysm. World J Surg 15:240, 1991 52. Paty R, Smith AD: Gangrene and Fournier's gangrene. Urol Clin North Am 19:149, 1992 53. Pessa ME, Howard RJ: Necrotizing fasciitis. Surg Gynecol Obstet 161:357,1985
NECROTIZING SOFT-TISSUE INFECTIONS
607
54. Rapport Y, Himelfarb MZ, Zikk D, et al: Cervical necrotizing fasciitis of odontogenic origin. Oral Surg Oral Med Oral Pathol 72:15, 1991 55. Ray D, Cohle SD, Lamb P: Spontaneous clostridial myonecrosis. J Forensic Sci 37:1428, 1992 56. Rea WI, Wyrick WJ: Necrotizing fasciitis. Am Surg 172:957, 1970 57. Riseman JA, Zamboni WA, Ross DO: Hyperbaric oxygen therapy reduces mortality and the need for debridement. Surgery 108:847, 1990 58. Rudge FW: The role of hyperbaric oxygenation in the treatment of clostridial myonecrosis. Milit Med 158:80, 1993 59. Stamenkovic I, Lew PD: Early recognition of potentially fatal necrotizing fasciitis: The role of frozen section biopsy. N Engl J Med 310:1689, 1984 60. Stevens DL: Musher DM, Watson DA, et al: Spontaneous, nontraumatic gangrene due to Clostridium septicum. Rev Infect Dis 12:286, 1990 61. Still HM, Wray CH, Moretz WH: Selected physiologic amputation: A valuable adjunct in preparation for surgical operation. Ann Surg 171:143, 1970 62. Van Unnik AJM: Inhibition of toxin production in Clostridum perfringes in vitro by hyperbaric oxygen. Antonie Van Leeuwenhoek 31:181,1965 63. Willoughby R, Grenberg RN: The toxic shock syndrome and streptococcal pyrogenic exotoxins. Ann Intern Med 98:559, 1983 64. Wilson B: Necrotizing fasciitis. Am Surg 172:957, 1970 65. Wood TF, Potter MA, Jonasson 0: Streptococcal toxic shock-like syndrome: The importance of surgical intervention. Ann Surg 217:109, 1993
Address reprint requests to Anthony A. Meyer, MD, PhD Department of Surgery University of North Carolina 164 Burnett Womack Campus Box 7210 Chapel Hill, NC 27599-7210