Excerpt from Gas Gangrene

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Background

The terms gas gangrene and clostridial myonecrosis are used interchangeably and refer to infection of muscle tissue by toxin-producing clostridia. In 1861, Louis Pasteur identified the first clostridial species, Clostridium butyricum. In 1892 and later, Welch, Nuttall, and other scientists isolated a gram-positive anaerobic bacillus from gangrenous wounds. This organism, originally known as Bacillus aerogenes capsulatus, later became Bacillus perfringens, then Clostridium welchii. The organism is now named Clostridium perfringens. Gas gangrene gained recognition for its wartime incidence, during which only a paucity of civilian cases occurred. During World War I, gas gangrene complicated 6% of open fractures and 1% of all open wounds. These figures steadily decreased to 0.7% during World War II, 0.2% during the Korean War, and 0.002% during the Vietnam War; however, gas gangrene was nonexistent during the battle in the Falkland Islands in 1982.

The US military medicine has credited this to the mobility of the forward surgical teams (FSTs) in keeping up with the fast-moving military units. Despite several casualties caused by enormous firepower and improvised explosive devices (IEDs), no gas gangrene has been reported among US soldiers during the ongoing operation Iraqi Freedom. The lethality of war wounds has decreased from 24% during operation Desert Storm (1991) to an unprecedented 10% during operation Iraqi Freedom.

Pathophysiology

Gas gangrene is caused by an anaerobic, gram-positive, spore-forming bacillus of the genus Clostridium. C perfringens is the most common cause of gas gangrene. Other common clostridial species that cause gas gangrene include Clostridium bifermentans, Clostridium septicum, Clostridium sporogenes, Clostridium novyi, Clostridium fallax, Clostridium histolyticum, and Clostridium tertium.

These organisms are true saprophytes and are ubiquitous in soil and dust. Clostridia have been isolated from the mucous membranes of humans, including the GI tract and the female genital tract. Clostridia also may colonize the skin, especially around the perineum. Clostridia are obligate anaerobes, but some species are relatively aerotolerant. Bacterial multiplication and the production of soluble proteins called exotoxins require a low oxygen tension.

Other bacteria are also capable of producing gas, and nonclostridial organisms have been isolated in 60-85% cases of gas gangrene. A recent clinical series on gas gangrene demonstrated a predominance (83.3%) of aerobic gram-negative bacilli in wound cultures compared with anaerobic gram-positive bacilli, with Clostridium species accounting for 4.5% of the isolates. The most frequently identified aerobic gram-negative bacteria were Escherichia coli, Proteus species, Pseudomonas aeruginosa, and Klebsiella pneumoniae.

C perfringens produces at least 20 exotoxins. The most important exotoxins and their biologic effects are as follows:

• Alpha toxin - Lethal,* lecithinase, necrotizing, hemolytic, cardiotoxic
• Beta toxin - Lethal,* necrotizing
• Epsilon toxin - Lethal,* permease
• Iota toxin - Lethal,* necrotizing
• Delta toxin - Lethal,* hemolysin
• Phi toxin - Hemolysin, cytolysin
• Kappa toxin - Lethal,* collagenase, gelatinase, necrotizing
• Lambda toxin - Protease
• Mu toxin - Hyaluronidase
• Nu toxin - Lethal,* deoxyribonuclease, hemolytic, necrotizing
• *Lethal as tested by injection in mice

The precise role of these exotoxins in the pathogenesis of gas gangrene is not entirely clear; however, alpha-toxin is apparently of utmost importance. The alpha-toxin is a 370-residue zinc metalloenzyme that has phospholipase-C activity (ie, lecithinase) and causes cell destruction by hydrolysis of key cell membrane components. This toxin can cause lysis of erythrocytes, leukocytes, platelets, fibroblasts, and muscle cells. Strains that do not produce this toxin are less virulent, underscoring its importance. Purified alpha-toxin has a myocardial suppressant effect in vitro and causes shock when injected into animals.

The phi-toxin is a hemolysin. Although it does not directly suppress myocardial function in vitro, it contributes to myocardial suppression in vivo, possibly by increasing the synthesis of secondary mediators which do suppress myocardial function in vitro. At higher concentrations, the phi-toxin can cause extensive cellular degeneration and direct vascular injury.

The kappa-toxin produced by C perfringens is a collagenase responsible for destruction of blood vessels and connective tissue. Other toxins include a deoxyribonuclease and hyaluronidase.

Contamination with clostridial spores in posttraumatic or postoperative lesions establishes the initial stage of infection. Local wound conditions are more important than the degree of clostridial contamination in the development of gas gangrene. Disrupted or necrotic tissue provides the necessary enzymes and a low oxidation/reduction potential, allowing for spore germination. Foreign bodies, premature wound closure, and devitalized muscle reduce the spore inoculum necessary to cause infection in laboratory animals.

The typical incubation period for gas gangrene frequently is short (ie, <24 h), but incubation periods of 1 hour to 6 weeks have been reported. Self-perpetuating destruction of tissue occurs by the presence of a rapidly multiplying microbial population and the production of locally and systemically acting exotoxins. Local effects include necrosis of muscle and subcutaneous fat and thrombosis of blood vessels. Marked edema may further compromise blood supply to the region. Fermentation of glucose probably is the main mechanism of gas production in gas gangrene. In C septicum spontaneous gas gangrene, nitrogen is the predominant gas component (74.5%), followed by oxygen (16.1%), hydrogen (5.9%), and carbon dioxide (3.4%). Production of hydrogen sulfide and carbon dioxide gas begins late and dissects along muscle bellies and fascial planes. These local effects create an environment that facilitates rapid spread of the infection.

Systemically, exotoxins may cause severe hemolysis. Hemoglobin levels may drop to very low levels and, when occurring with hypotension, may cause acute tubular necrosis and renal failure. A rapidly progressive infection can cause a patient to progress quickly into shock. The mechanism of shock is poorly understood. Unconcentrated filtrate from C perfringens, purified alpha-toxin, and purified phi-toxins cause hypotension, bradycardia, and decreased cardiac output when injected into laboratory animals. Because alpha-toxins and phi-toxins are lipophilic and may remain locally bound to tissue plasma membranes, the toxins may stimulate synthesis of secondary mediators, which cause cardiovascular abnormalities.

Frequency

United States

Clostridia species are ubiquitous and widely distributed in the soil, especially in cultivated land. The density of clostridia in the soil is a contributing factor in the development of trauma-related gas gangrene. Civilian cases of gas gangrene are more common, with approximately 3000 cases per year. Gas gangrene can be classified as posttraumatic, postoperative, or spontaneous. Posttraumatic gas gangrene accounts for 60% of the overall incidence; most cases involve automobile accidents.

From 1998-2002, C septicum was implicated in causing serious infections in recipients of contaminated musculoskeletal-tissue allografts. Recently, Clostridium sordellii, an infrequent human pathogen, caused fatal toxic shock syndrome, bacteremia, and extensive endometritis in 4 young women who underwent medical abortion with oral mifepristone and vaginal misoprostol.

International

During April-June 2000, several injection-drug users in Scotland, Ireland, and England developed serious clostridial infections (C novyi and C perfringens) complicated by a high mortality rate (97%).

Mortality/Morbidity

Gas gangrene is undoubtedly an infection with very high mortality. The reported mortality rates vary widely, with a mortality rate of 25% in most recent studies. It can be 100% in patients with spontaneous gas gangrene or those with delayed treatment.

Sex

The sex of the individual does not affect the outcome.

Age

Although age is not a prognostic factor, advanced age and comorbid conditions are associated with higher mortality.

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