Necrotizing soft tissue infections: a guide to early diagnosis and initial therapy.

Abstract: Necrotizing skin and soft tissue infections are caused by many different bacteria, are frequently polymicrobial, and may have a deceptively innocent early clinical presentation. Clostridial and nonclostridial necrotizing infections are frequently similar in their early presentation. The initial presentation of these infections can be insidious, which results in delay in diagnosis and the start of therapy. The clinician must use sound medical principles of clinical history and meticulous examination in each patient, combined with constant suspicion, to establish a timely diagnosis. This group of infectious diseases is associated with frequent morbidity and significant mortality rates, which increase with any delay in the diagnosis and the initiation of medical and surgical therapy. Also associated with these necrotizing infections is an excessive index of litigation. This review is intended as a guide for the clinician in making an early diagnosis of any necrotizing skin and soft tissue infection and initialing effective medical and surgical therapy.

Key Words: early diagnosis and treatment, necrotizing soft tissue infection

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Necrotizing infections (NIs) are uncommon and difficult to diagnose, and they cause progressive morbidity until the infectious process is diagnosed and treated medically and surgically. (1,2) Many physicians may never see a case of NI during their clinical careers, but all physicians need to understand the syndrome. Unfortunately, the literature addressing NI contains confusing information, inaccurate bacteriologic data, and antiquated antibiotic therapy. A delay in diagnosis is associated with a grave prognosis and increased mortality. (1,2) When the diagnosis of NI is missed or delayed, there is a probability of a lawsuit in our increasingly litigious society. (3) This review was written to guide the clinician toward evaluation of the disease process, obtain appropriate tests, and implement initial medical and surgical treatment. By following a standard evaluation of a suspicious or routine infection, the uncommon diagnosis of necrotizing soft tissue infection can be made by a physician who has never seen a patient with NI. The main goal of the clinician must be to establish the diagnosis and initially treat the patient within the standard of care. The primary care physician should obtain a consultation with an infectious disease physician and a surgeon, both of whom must have clinical experience in the treatment of NI. The medical record must be legible and well documented.

Classification of Necrotizing Infections

A spectrum of infections diseases result in necrosis of skin and soft tissue. These NI include clostridial infections, which are rare, or necrotizing soft tissue infections of various types, which are more common. The broad categories within the latter group include necrotizing fasciitis, bacterial synergistic gangrene, and streptococcal gangrene. This entire spectrum of NIs should be designated as "infectious gangrenes" or "necrotizing soft tissue infections" and initially should be evaluated and managed according to a common approach to eliminate any delay in treatment and to reduce the possible administration of ineffective therapy. The most important clinical approach for any skin and soil tissue infection includes suspicion of possible necrotizing soft tissue infection.

This one basic but important consideration can decrease the morbidity and mortality attributable to these unusual diseases by leading the clinician to consider the diagnosis early. Once the diagnosis is considered, the clinician should pursue an appropriate evaluation to confirm or eliminate the diagnosis of NI. Loss of life or the development of a severe disability as a result of this group of NIs is a prime generator of malpractice claims. (3) Unfortunately, the literature regarding skin and soft tissue NIs is confusing, contains errors and misinterpreted data, and includes the use of nonstandard or outdated terms in historical articles such as hospital gangrene, Meleney's gangrene, suppurativa fasciitis, necrotizing erysipelas, and acute dermal gangrene.

Bacteriology 

The bacteriology of the various disease processes included in the infectious gangrenes is complex. The majority of NIs resulting in necrotizing fasciitis consist of a mixture of [beta]-hemolytic streptococci (90%), anaerobic Gram-positive cocci, aerobic Gram-negative bacilli, and Bacteroides species. A single organism, with the unusual exception of Group A [beta]-hemolytic streptococci (GAS), rarely causes an infection resulting in necrotizing fasciitis. Necrotizing fasciitis occurs when a mixed variety of organisms--aerobic and anaerobic--invade the subcutaneous tissue and fascia in a synergistic fashion. The actual organisms and specific conditions essential for the development of these necrotic processes are still unknown. A good laboratory model of soft tissue NIs does not exist. Much of the bacteriologic data in the literature concerning these gangrenous infections are invalid, because the reports are outdated, use old methodology, and report organisms present as a result of frequent secondary infection caused by opportunistic organisms. Also, some hospital laboratories are unable to isolate and identify correctly the causative organisms; thus, false-negative reports also may be encountered. Most current reports, however, speculate that synergy between aerobic and anaerobic organisms is responsible for the necrosis of skin and soft tissue and the fascial destructive process of necrotizing fasciitis. As many as 6% of patients with invasive GAS infection may develop necrotizing fasciitis. (4)

Bacterial synergistic gangrene is primarily a subcutaneous gangrenous infection caused by the same organisms as those that cause necrotizing fasciitis, but there is no involvement of any fascial tissue. Classically, cultures yield the combination of a microaerophilic nonhemolytic streptococcus in the spreading periphery of the lesion and Staphylococcus aureus found in the zone of gangrene. Streptococci can be accompanied by a variety of other organisms, such as Proteus, Enterobacter. Pseudomonas, and Clostridium species. Streptolysin S-producing strain of Group G hemolytic streptococci recently was reported to produce NI. (5) The clinical course of bacterial synergistic gangrene is frequently slow but initially should be treated as an infectious gangrene until the lack of fascial involvement is recognized. Bacterial synergistic gangrene should then be treated conservatively, although all necrotic tissue initially must be surgically removed. Streptococcal gangrene is caused only by toxigenic strains of GAS. Acute streptococcal gangrene is usually a rapidly advancing gangrenous infection associated with severe toxic symptoms (eg, streptococcal toxic shock syndrome).

Clostridial and mycotic infections must be considered in any initial evaluation of skin and soft tissue NIs, despite their relatively rare occurrence. Clostridial infections should be suspected when necrotic muscle is found during debridement of an infectious gangrene with severe systemic toxicity associated with clinical central nervous system manifestations. Patients with maliganancies are particularly prone to NIs caused by Clostridium septicum. (6) NIs can be caused by marine vibrio species, but cases are rare and usually are associated with chronic liver disease and immune-compromised states. Mucormycosis (ie, Zygomycetes infection) can produce an aggressive gangrenous infection because of its ability to invade directly and thrombose blood vessels, which results in infarction of tissue. Initial microbiologic cultures may be contaminated with secondary infecting organisms if the skin barrier is broken or if the infection occurs in the perineal area.

Diagnosis

A difficult problem for the clinician in evaluating any skin or soft tissue NI is the frequent lack of any diagnostic external signs or symptoms suggestive of NI. NIs may present as mild cellulitis or a small ulcer (Table 1). Events predisposing patients to soft tissue NIs include mild trauma, insect bites, drug reactions, illicit drug injections, perirectal abscesses, major traumas, and surgical procedures. (7) NIs may occur in patients in whom there is no apparent inciting event or portal of entry. The most frequent spontaneous site of the infectious gangrenes is in the perineum, but the extremities are the most common sites of involvement. (1,4) The frequent association of soft tissue NIs with underlying chronic diseases such as diabetes mellitus, hypertension, congestive heart failure, obesity, renal insufficiency, cancer, malnutrition, arteriosclerosis, alcoholism, autoimmune disease, acquired immunodeficiency syndrome, and immunosuppression, as well as with patients older than 60 years of age, is diagnostically helpful. These skin and soft tissue NIs do occur in healthy individuals as much as 30% of the time, however. (4)

Neither clostridial nor nonclostridial infections initially demonstrate prominent external evidence of skin death. Severe pain and systemic symptoms that occur out of proportion to the local infection characterize clostridial infections. As the clostridial infection progresses, the skin may develop a bronze color, followed by hemorrhagic bullae, then dermal gangrene, and finally crepitus. Clostridial exotoxins produce extensive tissue necrosis, with minimal hyperemia, fibrin formation, or neutrophil infiltration seen within the affected tissue. Nonclostridial infections are most likely to be associated with erythema, pain, and swelling but frequently are initially identical to simple cellulitis. Failure to respond to antibiotics, rapid progression, or evolving systemic signs of infection are significant clues that NI may be present.

The clinical history and a meticulous physical examination are essential to establish an early diagnosis of necrotizing skin and soft tissue NIs. The patient generally appears ill and has a rapid pulse and significant temperature elevation. An occasional unique finding of necrotizing fasciitis is numbness of the involved area. Skin anesthesia probably is due to infarction of the cutaneous nerves located in necrotic subcutaneous fascia and soft tissue. Some patients with necrotizing fasciitis may present with localized pain of the involved site, and the overlying skin is erythematous, hot, and edematous.

An apparent superficial cellulitis that fails to respond to standard therapy must raise suspicion of a more extensive underlying subcutaneous infection. Moderate to severe pain of the skin of an infected area is characteristic of GAS infections that develop into streptococcal gangrene. Excruciating pain is a significant clinical symptom of clostridial myonecrosis. Thrombocytopenia and sepsis are common in patients with any of the gangrenous infections. Hypocalcemia is occasionally noted, but rarely are there any accompanying symptoms of muscle twitching, Chvostek sign, or carpopedal spasm. (4) All patients have leukocytosis with a preponderance of neutrophils. An admission white blood cell count greater than 14 x [10.sup.9]/L, serum sodium less than 135 nmol/L, and blood urea nitrogen greater than 15 mg/dl have been reported to be consistent findings associated with necrotizing fasciitis (8) (Table 2). Frequently, the presence of gas in the subcutaneous and soft tissue is noted radiographically. The clinical sign of crepitus is found in 50% of patients. Bullae, skin necrosis, seropurulent exudates, and foul odor are common in the late presentation of skin and soft tissue NIs. Most patients have hypoproteinemia and hypoalbuminemia. Electrolyte and fluid deficits are frequent, even though no external loss of fluid occurs. Edema occurs with the infectious gangrenes and results in clinical hypovolemia and occasional hypotension. Admission laboratory values associated with patient mortality are increased serum creatinine greater than 2 mg/dl and increased blood lactate level. (9)

Soft tissue NIs can be diagnosed reliably on the basis of a variety of methods (Table 3). Computed tomographic (CT) scans provide an accurate picture of the presence and the extent of abnormal soft tissue gas dissecting along fascial planes, which is almost always diagnostic of necrotizing fasciitis. (10) Other suspicious findings evident on rapid helical CT scanning of necrotizing soft tissue infections include fascial thickening, fascial stranding, and asymmetric thickening of fascial planes. (10) Magnetic resonance imaging (MRI) with gadolinium contrast enhancement can accurately determine the presence of necrosis of fascia and the extent of the infectious and necrotic process. (11) Unfortunately, the time required to obtain an MRI scan in an unstable patient with sepsis may be excessive and life-threatening. Any movement by the patient during MRI can render the time-consuming study difficult to interpret by the radiologist. MRI is therefore most useful in stable, conscious, cooperative, and not seriously septic patients. A bedside frozen tissue section biopsy is an expedient method by which to establish the diagnosis on the basis of typical histologic changes of subcutaneous necrosis, polymorphonuclear cell infiltration, fibrinous vascular thrombosis with necrosis, microorganisms within the destroyed fascia and dermis, and sparing of muscle. (12,13) Biopsy can also identify fungus in the tissue and fungal invasion with thrombosis of blood vessels. Tissue biopsy with Gram's slain of the exudate may also reveal the characteristic finding of clostridia organisms, which appear as Gram-positive rods with blunt ends resembling boxcars. The clinician should never hesitate to call in the pathologist for frozen tissue section evaluation at night or on the weekend. Fine-needle or large-bore needle aspiration is another method by which to establish the diagnosis and direct antimicrobial therapy. (14) Inability to obtain fluid, however, is nondiagnostic and does not rule out NI. Tense edema of an extremity should be evaluated by measuring muscle compartment pressure. (15) Easy passage of a probe along a plane between the subcutaneous tissue and deep muscle is suggestive of necrotizing fasciitis. (16)

As any infectious gangrenous process advances, systemic toxicity develops. Toxic shock syndrome occurs in almost 10% of patients with massive GAS infections. (4) Progression of the occlusive microvascular process produces delayed cutaneous gangrene. If prompt and accurate treatment is not established, the condition advances into systemic sepsis and fatal multiple organ system failure. A seroma with partial or complete dehiscence of a recent operative incision are potentially suggestive of NI. The patient should be returned to the operating room for tissue biopsy and thorough examination of all layers of the skin, subcutaneous tissue, fascia, muscle, and peritoneum. Examination of postoperative wounds while the patient is under local anesthesia with a gloved hand in the patient's bed is associated with incorrect assessment of the type or extent of the infectious process and results in delay in both the diagnosis and the definitive treatment of infectious gangrene.

Treatment

To start treatment of patients with NI, the physician must ultimately suspect and establish the diagnosis. Several reliable diagnostic tests are available: CT and MRI scans, tissue biopsy, and needle aspiration. Suspicion of a possible NI process is the clinician's most important defense against delayed or missed diagnosis. Consultations from an infectious disease specialist along with a surgeon with clinical experience with NIs are necessary. A negative consult is more valuable to the patient and the primary physician than a delayed diagnosis, which is associated with significant morbidity and mortality.

Once the diagnosis is established, treatment of the patient usually is best managed by a team comprising the infectious disease and critical care specialists and the surgeon (Table 4). Under the preliminary guidance of Gram-stained smears while aerobic and anaerobic tissue and blood cultures are in progress, a triple regimen of IV antibiotic coverage (17,18) is appropriate to cover the diverse and varied causative bacteria:

* Penicillin or ampicillin for clostridia, streptococci, and Peptostreptococcus.

* Clindamycin (Cleocin; Pharmacia & Upjohn, Kalamazoo, MI) or metronidazole (Flagyl; G.D. Searle & Co., Skokie, IL) for anaerobes, Bacteroides fragilis, Fusobacterium, and Peptostreptococcus. Clindamycin may be useful for treating GAS in patients with the toxic streptococcus syndrome because it inhibits toxin production.

* Gentamicin (Garamycin; Schering-Plough International, Kenilworth, NJ) or another aminoglycoside for Enterobacteriaceae (ie, Gram-negative organisms). Gentamicin has a synergistic effect with penicillin against streptococci.

Imipenem (Primaxin; Merck & Co., lnc., Whitehouse Station, NJ) and meropenem (Merrem; AstraZeneca Pharmaceuticals LP, Wilmington, DE), by virtue of their high [beta]-lactamase resistance, wide-spectrum efficacy, and inhibition of endotoxin release from aerobic (ie, Gram-negative) bacilli, may be the initial agents of choice for treatment of the frequent polymicrobial infections that result in necrosis or skin and soft tissue. (17) Postoperative antibiotic coverage is adjusted on the basis of microbiologic testing results from cultures of tissue and blood. The most common organisms not adequately covered by initial antibiotic therapy are enterococci. (18) Tetanus prophylaxis with absorbed tetanus toxoid and passive immune coverage with tetanus hyperimmune globulin are indicated in the management of all high-risk wounds, because tetanus is an occasional complication of necrotizing lesions of any infectious gangrenes. Patients with mucormycosis and progressive necrotizing lesions are at high risk of death. Once invasive mucormycosis has been demonstrated, treatment with amphotericin B (Fungizone; Bristol-Myers Squibb, New York, NY) or liposomal formulations for patients with renal dysfunction must be started promptly.

Clostridial infections may initially be recognized at the time of surgery by the identification of necrotic muscle. Complete debridement of all necrotic tissue must be performed in NIs during the initial operative procedure. Amputation of an extremity should be considered early in the treatment of clostridial gangrenous infections, because it may be lifesaving. High-dose IV penicillin should be administered; clindamycin or metronidazole is substituted for patients with penicillin allergy. Hyperbaric oxygenation should be administered alter surgery to the patient with clostridial gangrene, because it is bacteriostatic to the clostridial organism and seems to hinder the production of [alpha] toxin. (19) Residual necrotic tissue left after debridement of clostridial gangrene reduces or neutralizes the beneficial effect of hyperbaric oxygenation. Hyperbaric oxygenation has been shown in nonclostridial soft tissue NIs to only shorten the time until wound closure alter surgical debridement. (18) Therefore, it is important to emphasize that primary treatment in all patients with infectious gangrene is meticulous, complete surgical debridement at the initial surgical procedure.

Once the diagnosis of necrotizing skin and soft tissue infection is made or highly suspected, fluid resuscitation and cardiovascular stabilization of the patient is necessary before surgery. Frequently, this requires placement of a central line or a Swan-Ganz catheter and preoperative fluid resuscitation in an intensive care unit if the patient is unstable. Appropriate IV antibiotics are always administered preoperatively. GAS necrotizing fasciitis may occasionally respond to IV [gamma]-globulin, but its use remains controversial. (20)

The management of any infectious gangrene requires an urgent surgical procedure. As soon as the patient's condition permits administration of a general anesthetic, complete surgical debridement of the area is performed in the operating room. Occasionally, a patient may remain in septic shock after resuscitation and IV antibiotics are initiated. Surgical debridement should not be delayed, because correction of the septic state may not occur until the infectious gangrenous process is completely excised.

The surgeon always follows three surgical principles: complete excision of all necrotic tissue, establishment of wide surgical drainage, and meticulous attention to hemostasis. (17) Time is a critical element in the successful treatment of patients with soil tissue NIs. Early recognition and aggressive medical and surgical therapy are the primary determinants of successful outcome in the treatment of all patients with skin and soft tissue NIs. Delay in the time from admission until the first complete surgical debridement significantly increases morbidity and mortality as a result of any skin and soft tissue NI. (1-3,7-9,12,13,17,18)

Key Points

* Necrotizing infections include clostridial infections, necrotizing fasciitis, bacterial synergistic gangrene, and streptococcal gangrene.

* The most important clinical approach to treating any skin and soft tissue infection includes suspicion of a possible necrotizing soft tissue infection.

* The difficult problem for the clinician evaluating any skin or soft tissue infection is the lack of any diagnostic external signs or symptoms suggestive of necrotizing infections.

* Several reliable diagnostic tests for necrotizing infection are available to the physician today: computed tomographic and magnetic resonance imaging scans, tissue biopsy, and needle aspiration.

Table 1. Early and late physical findings associated with necrotizing
soft tissue infections

Early physical findings               Late physical findings
  Cellulitis or small ulcer             Tense edema
  Erythema, warmth, and edema in
    overlying skin                      Bronze to purplish discolora-
                                          tion of skin progressing to
                                          hemorrhagic bullae
  Skin anesthesia                       Crepitus
  Localized pain of the involved
    site                                Hypotension
  Hyperthermia                          Seropurulent exudate (ie,
                                          "dishwater pus")
  Tachycardia                           Foul odor
  Diffuse swelling of area of
  necrotizing soft tissue infection     Dehydration
                                        Severe pain and systemic sym-
                                          ptoms out of proportion to
                                          local infection are characte-
                                          ristic of clostridial infec-
                                          tion or streptococcal
                                          gangrene
                                        Failure of a skin or soft
                                          tissue infection to respond
                                          to antibiotics
                                        Rapid progression of infectious
                                          process
                                        Dermal gangrene or necrosis
                                        Soft tissue or fascial necrosis
                                        Systemic toxicity
                                        Systemic inflammatory response
                                          syndrome
                                        Multiple organ systern failure

Table 2. Admission laboratory and radiographic
findings frequently associated with necrotizing soft
tissue infection (a)

Admission laboratory findings
  WBC count > 14 x [10.sup.9]/L (b)
  Serum sodium < 135 nmol/L (b)
  BUN > 15 mg/dl (b)
  Thrombocytopenia
  Hypocalcemia
  Hypoproteinemia
  Hypoalbuminemia
  Elevated serum glucose
  Hemoglobin < 10 g/dl
  Hypocholesterolemia (c)
  Serum creatinine > 2 mg/dl (c)
  Increased blood lactate (c)
Radiographic finding
  Gas in the subcutaneous and soft tissue

(a) WBC, white blood cell; BUN, blood urea nitrogen.

(b) Suggestive of necrotizing fasciitis. (8)

(c) Associated with increased mortality. (9)

Table 3. Diagnostic evaluation of suspected necrotizing
skin and soft tissue infections

Computed tomography (10)
Magnetic resonance imaging with intravenous gadolinimn contrast
  medium (11)
Incisional tissue biopsy with frozen section evaluation; Gram's stain
  and microbiologic culture of tissue and exudates (13)
Fine-needle or large-bore needle aspiration with Gram's stain and
  culture of aspirate (14)
Measurement of extremity muscle compartment pressure (15) (Elevated
  compartment pressure of > 40 mm Hg mandates immediate
  fasciotomy.)
Probe of any suspicious opening in the skin (16)

Table 4. Initial treatment of necrotizing infection (a)

Clinical history and physical examination
WBC count, serum electrolytes, serum calcium
X-ray of area of suspected necrotizing soft tissue infection
Consultation with
  Infectious disease physician familiar with necrotizing infections
  Surgeon Familiar with necrotizing infections
Aerobic and anaerobic culture with Gram's stain
Central line and Foley catheter placement
Fluid resuscitation, cardiovascular stabilization, and preoperative
  preparation
Intravenous antibiotics before surgical debridement
Tetanus prophylaxis
Complete radical surgical debridement of all necrotic tissue during
  initial operative procedure
Postoperative nutritional evaluation and administration of enteral or
  parenteral hyperalimentation
Postoperative physical therapy

(a) WBC, white blood cell.

References

(1.) Lille ST, Sato TT, Engrav LH, et al. Necrotizing soil tissue infections: Obstacles in diagnosis, J Am Coll Surg 1996:182:7-11.

(2.) Majeski JA, Alexander JW. Early diagnosis, nutritional support, and immediate extensive debridement improve survival in necrotizing fasciitis. Am J Surg 1983;145:784-787.

(3.) Fink S, Chaudhuri TK, Davis HH. Necrotizing fasciitis and malpractice claims. South Meal J 1999:92:770-774.

(4.) Ben-Abraham R, Keller N, Vered R, et al. Invasive Group A streptococcal infections in a large tertiary center: Epidemiology, characteristics and outcome, Infection 2002;30:81-85.

(5.) Humar D, Datta V, Bast DJ, et al. Streptolysin S and necrotising infections produced by Group G Streptococcus. Lancet 2002;359:124-129.

(6.) Kornbluth AA, Danzig JB, Bernstein LH. Clostridium septicum infection and associated malignancy: Report of 2 cases and review of the literature. Medicine (Baltimore) 1989;68:30-37.

(7.) Bosshardt TL, Henderson VJ, Organ CH Jr. Necrotizing soft-tissue infections. Arch Surg 1996;131:846-854.

(8.) Wall DB, de Virgilio C, Black S. et al. Objective criteria may assist in distinguishing necrotizing fasciitis from nonnecrotizing soft tissue infection. Am J Surg 2000;179:17-21.

(9.) Elliott DC, Kufera JA, Myers RA. Necrotizing soft tissue infections: Risk factors for mortality mad strategies for management. Ann Surg 1996;224:672-683.

(10.) Wysoki MG, Santora TA, Shah RM, et al. Necrotizing fasciitis: CT characteristics. Radiology 1997;203:859-863.

(11.) Brothers TE, Tagge DU. Stutley JE, et al. Magnetic resonance imaging differentiates between necrotizing and non-necrotizing fasciitis of the lower extremity. J Am Coll Surg 1998;187:416-421.

(12.) Stamenkovic I, Lew PD. Early recognition &potentially fatal necrotizing fasciitis: The use of frozen-section biopsy. N Engl J Med 1984;310: 1689-1693.

(13.) Majeski J. Majeski E. Necrotizing fasciitis: Improved survival with early recognition by tissue biopsy and aggressive surgical treatment. South Med J 1997;90:1065-1068.

(14.) Lee PC, Turnidge J, McDonald PJ. Fine-needle aspiration biopsy in diagnosis of soft tissue infections. J Clin Microbiol 1985;22:80-83.

(15.) Bisno AL, Stevens DL. Streptococcal infections of skin and soft tissues. N Engl J Med 1996;334:240-245.

(16.) Baxter CR. Surgical management of soft tissue infections. Surg Clin North Am 1972;52:1483-1499.

(17.) Majeski JA. Necrotizing infections of the skin and soft tissue, in Cameron JL: Current Surgical Therapy. St. Louis, Mosby, 2001, ed 7, pp 1246-1250.

(18.) Elliott D, Kufera JA, Myers RA, The microbiology of necrotizing soft tissue infections. Am J Surg 2000;179:361-366.

(19.) Chapnick EK, Abter EI. Necrotizing soft-tissue infections, Infect Dis Clin North Am 1996;10:835-855.

(20.) Stevens DL, Kaplan EL. Life-threatening streptococcal infections, in Stevens DL, Kaplan EI, (eds): Streptococcal Infections: Clinical Aspects, Microbiology, and Molecular Pathogenesis. New York, Oxford University Press, 2000, pp 164-176.

From the Surgical Services and the Medicine Specialty Service, Charleston Veterans Affairs Hospital, Charleston, SC.

Reprint requests to James A. Majeski, MD, PhD, 900 Bowman Road, Suite 100, Mr. Pleasant, SC 29464-3203. Email: [e-mail]

Accepted February 10, 2003.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9609-0900