Description of the condition
Gas gangrene is an acute, severe, painful condition in which the muscles and subcutaneous tissues become filled with gas and serosanguineous exudate (i.e. blood serum that appears pink because it contains a small number of red blood cells) (see Glossary: Appendix 1) (Anderson 2007). It is not caused by exposure to gas, but is the result of infection by specific bacteria that invade muscle tissue, and produce exotoxins (potent toxins secreted by the micro-organism) (Appendix 1), particularly one called 'alpha toxin' - a membrane-disrupting toxin with phospholipase C activity - that causes tissue necrosis (death) (Appendix 1) and gas (Stevens 1988). Gas gangrene is also called 'Clostridial myonecrosis' because Clostridium species are the most common etiologic agents (cause).
Pathogens and etiology
Gas gangrene can be grouped into clostridial and non-clostridial forms, depending on the type of bacteria causing the condition.
Clostridium species are Gram-positive, spore-forming, anaerobic bacilli commonly found in soil, and dust, that are also found in the gastrointestinal tract, vagina and on the skin of humans (Xiao 2008). The most common subtype of Clostridium, which causes clostridial gas gangrene, isClostridium perfringens, previously known as C welchii. Other Clostridium species, including C novyi, C septicum, C histolyticum, C bifermentans and C fallax, are also responsible for the condition (De 2003).
Non-clostridial species of bacteria are able to produce gas, and have also been implicated in causing gas gangrene. These non-clostridial organisms are mainly aerobic and Gram-negative, and include Escherichia coli, Proteus species, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterococcus species, and Bacteroides species (Bessman 1975; Hart 1983; De 2003).
In most cases of gas gangrene, pathogens invade the tissues through trauma wounds, while the remainder arise spontaneously or from surgical procedures (Hart 1990). Spontaneous gas gangrene is often caused by the haematogenous spread (i.e. through the blood) (Appendix 1) of C septicum, which is relatively aerotolerant (tolerates oxygen), and thus more capable of initiating infection in the absence of obvious damage to tissues. The portal of entry to the blood stream is believed to be mucosal ulceration, or, in patients with colon disease, perforation of the gastrointestinal tract (Leung 1981; Stevens 1990). The usual manifestation is a necrotizing infection in an extremity or in the abdominal wall, accompanied by hypotension and renal failure (Gerding 2011). When tissue is damaged in people who have undergone trauma or had surgery, the vascular supply may be compromised, which leads to a lowering of the oxygen tension within the tissues, thus providing circumstances in which micro-organisms readily multiply. Under conditions of low oxygen levels these organisms produce and release a variety of exotoxins, including lecithinase, collagenase, hyaluronidase, fibrinolysin and haemagglutinin, which can lead to local and systematic (whole body) changes in the affected patients. The alpha-toxin, a C-lecithinase, which is a major lethal toxin in gas gangrene, leads to necrosis and haemolysis (breakdown of blood) that can subsequently cause anaemia, jaundice and even renal failure. Other exotoxins also play an important role in destroying and liquefying healthy tissue, and in the rapid spread of infection (Hart 1990).
Historically, gas gangrene has been a complication of battlefield injuries. The incidence associated with war wounds was 5% in World War I, 0.7% in World War II, 0.2% in the Korean War, and 0.02% in the Vietnam War (Bartlett 2007). Nowadays, battlefield gas gangrene is not a major cause for concern, but C perfringens or its toxins are a possible biological weapon (Titball 2005). In civilian practice incidence of gas gangrene remains relatively high due to people being less cautious about infection, an absence of standard treatment away from the battlefield environment, and an increasing proportion of elderly people and people with diabetes (Brown 1974; Titball 2005).
Traumatic injuries account for about 50% of civilian cases of gas gangrene, with vehicular accidents accounting for the majority (about 70%); the remaining cases develop in people after crush injuries, industrial accidents, gunshot wounds, and burns. Postoperative complications account for about 30% of cases, and are most frequently associated with surgery on the appendix, biliary tract, or intestine. Approximately 20% are spontaneous and associated with an occult (apparently symptom-free, so 'hidden', and not known about) colonic malignancy (Bartlett 2007; Gerding 2011). The estimated number of cases in the United States is about 1000 per year (Gerding 2011). Several cases of gas gangrene have been also reported in injecting drug users in Scotland (McGuigan 2002), patients undergoing liposuction in Germany (Lehnhardt 2008), and earthquake survivors in China (Wang 2010).
Gas gangrene carries a high fatality rate ranging from 25% in those with trauma, to nearly 100% in those who do not receive treatment (Melville 2006; Gerding 2011). Inadequate treatment, advanced age, location on the trunk, severe underlying disease, and shock are factors that increase the risk of a poor prognosis with gas gangrene (Gerding 2011). There is no indication from current studies that gender or race differences have an effect on the prognosis.
Early diagnosis is the most crucial part of successful management of gas gangrene.
A diagnosis of gas gangrene can be suspected, until proven otherwise, when the following features are present: history of prior trauma or surgery, muscle swelling, severe pain, oedema (swelling due to accumulation of fluid), wound discolouration, watery discharge, haemorrhagic bullae (elevated blisters, usually exceeding 5 mm in diameter, filled with blood) (Appendix 1), malodour (unpleasant smell) (Appendix 1) and crepitus (a crackling sound) (Appendix 1) (Altemeier 1971; Hart 1990). A Gram-stain of wound exudate is considered to be the most rapid means of confirming the suspected diagnosis (Hart 1990). Diagnosis should also involve histopathologic examination of the lesion for myonecrosis (necrotic damage) without polymorphonuclear leukocytes (a type of white blood cell), and imaging methods that find gas in the tissue (Gerding 2011). Anaerobic (oxygen-free) cultures should be taken when the wound is debrided (trimmed of dead material) (Appendix 1) to confirm the identity of the pathogens, but treatment should be initiated before the findings are available, because it usually takes 48 to 72 hours for Clostridium spp to grow in culture media and a 24-hour delay in treatment can be fatal to patients with gas gangrene (Altemeier 1971; Hart 1990). Spontaneous gas gangrene with the culture of Clostridium septicum should be carefully investigated as it may have metastasised from the site of a gastrointestinal malignancy (Hart 1990).
Description of the intervention
Treating gas gangrene involves complex interventions encompassing immediate debridement, antibiotic treatment, hyperbaric oxygen (HBO) therapy and systemic support treatment (Schwartz 1978; Stevens 2005). Many authorities acknowledge that a combination of these interventions is necessary, although the relative importance of each intervention is still controversial ( Hart 1990). In addition, Chinese herbal medicine can be used as an adjunct treatment (Zhao 2004; Liu 2011).
How the intervention might work
Surgical debridement is considered to be the cornerstone of treatment for gas gangrene. Once gas gangrene is suspected, an aggressive debridement of all tissues involved should be carried out immediately for early diagnosis and treatment (Schwartz 1978). Early surgical intervention with multiple incisions and fasciotomy (incisions that are left open to relieve underlying pressure in the tissues) involves the removal of all compromised tissue, foreign bodies and haematoma (collections of blood) to allow decompression and drainage. Leaving the wounds wide open is necessary for aeration (oxygenation) (Hart 1990).
While myositis (inflammation of muscle) (Appendix 1) is still relatively localized, radical decompression of the fascial compartments involved - by free longitudinal incisions and excisions of the infected muscle - usually arrests the process, and eliminates the need for amputation in order to conserve a functional limb. Without timely debridement, gas gangrene may progress to extensive involvement of extremities, which may result in amputation (Altemeier 1971), though amputation does not apply to gas gangrene of the trunk, which has a much poorer prognosis, the aggressive debridement of compromised skin, muscle and fascia is still necessary (Morgan 1971).
Antibiotics are as important in the treatment of gas gangrene as surgical debridement (Hart 1983).
Studies in animals have shown that prompt treatment with antibiotics can significantly improve survival rates (Marrie 1981; Stevens 1987a). Historically in humans, penicillin G has been recommended in doses of between 10 and 24 million units per day (Holland 1975; Laflin 1976; Hart 1983). Currently, a combination of penicillin and clindamycin is widely used for treating clostridial gas gangrene (Stevens 2005). The rationale for using penicillin in combination with clindamycin is that some strains of Chlostridium are resistant to clindamycin, but will be susceptible to penicillin. Overall, clindamycin is thought to be the superior drug for reducing toxin formation (Gerding 2011). Some other types of antibiotics, including rifampin, metronidazole, chloramphenicol, and tetracycline, have been shown to be more effective in vitro or in animal studies (Stevens 1987a; Stevens 1987b).
These antibiotics provide a diverse array of mechanisms of action, including inhibition of: cell wall synthesis (penicillin), protein synthesis (chloramphenicol, tetracycline, and clindamycin), RNA synthesis (rifampin), and electron transport (metronidazole) (Stevens 1987b). In cases where patients are allergic to penicillin, chloramphenicol can be substituted to serve as an alternative (Schwartz 1978; Stevens 1987b).
Other, non-clostridial bacteria are frequently found in gas gangrene tissue cultures, so treatment that is active against Gram-positive (e.g. penicillin or cephalosporin), Gram-negative (e.g. aminoglycoside, cephalosporin, or ciprofloxacin), and anaerobic organisms (e.g. clindamycin or metronidazole) should be combined in the antibiotic therapy until the results of bacteriological culture are known (Folstad 2004; Trott 2005).
Hyperbaric oxygen (HBO) therapy
Hyperbaric oxygen (HBO) therapy is the medical use of oxygen at a pressure higher than atmospheric pressure. It can drastically increase the partial pressure of oxygen in body tissues, and is thought to be a beneficial adjunct treatment for gas gangrene (Hart 1983). In evidence derived from In vitro experiments and animal models, HBO therapy has been reported to enhance survival, and exert a direct bactericidal effect on most Clostridium species by inhibiting alpha-toxin production (Van Unnik 1965; Kaye 1967; Demello 1973; Hart 1983; Hirn 1993; Stevens 1993). Another important role of HBO is to relieve the hypoxic (oxygen-poor) environment of surrounding ischaemic tissue, so limiting the extent of necrosis (Hart 1990). Similar results have been reported in many retrospective studies of HBO therapy added to surgery and antibiotic treatment in patients with gas gangrene (Hart 1983; Shupak 1984; Korhonen 1999). Giving HBO therapy has even been recommended before initial debridement on the basis of experimental evidence and the results of favourable clinical experience (Holland 1975).
However, the results of two retrospective multicentre studies did not demonstrate a survival advantage with HBO therapy for major necrotizing infections, such as gas gangrene (Brown 1994; George 2009). A systematic review that evaluated the efficacy of HBO for treating hypoxic wounds concluded that the therapeutic effect of HBO is still unclear due to an absence of high-quality trials (Wang 2003).
HBO, as well as being a treatment with questionable efficacy, may increase the risk of some adverse events including oxygen toxicity, barotrauma (damage caused by pressure differences between air spaces and fluids within the body) (Appendix 1), decompression sickness, and pulmonary damage, most of which, however, seem reversible and self-limiting (Hart 1990; Tibbles 1996).
The recommended pressure used in HBO therapy ranges from 2 to 3 atmospheres absolute pressure (ATA), and the exposure time ranges from 90 minutes, with 100% oxygen, to between five and 12 hours with periodic air breaks (Hart 1990). Clinical and experimental evidence has suggested that patients treated with 3 ATA for 90 minutes benefit from more conservative surgery and less extensive amputation, so treatment with this regimen may be preferred (Tibbles 1996). Patients may tolerate exposure to oxygen pressures of up to 3 ATA for a maximum duration of 120 minutes (Tibbles 1996).
Systemic support treatment
Supportive measures are an essential part of the treatment for gas gangrene, including careful medical management and prompt therapy for complications of clostridial bacteraemia (bacteria in the blood) (Appendix 1) (Schwartz 1978).
Management of gas gangrene frequently involves volume expansion (of the blood) within the patient, with addition of intravenous fluid, plasma and blood. A high level of calories, protein and vitamins should be also administered (Xiao 2008). Shock is a frequent complication of gas gangrene, and rapid volume expansion may be required to deal with it. Monitoring central venous pressure (Appendix 1) or pulmonary capillary wedge pressure (Appendix 1) may be valuable in severely ill patients. Additionally, careful monitoring of electrolytes and packed cell volume (of blood) (Appendix 1) may be also necessary (Schwartz 1978; Hart 1990).
Chinese herbal medicine
Some authors have reported that internal and topical (surface) use of Chinese herbs accompanied with debridement and antibiotic therapy can reduce fatalities caused by gas gangrene (Zhao 2004; Liu 2011). Typically, traditional Chinese medicine consists of complex prescriptions of a combination of several herbal components. The mechanism of action of the herbal medicines is reported to involve haemostasis (prevention of bleeding), detumescence (subsidence of swelling) (Appendix 1) and antibacterial activity (Hou 2010). The efficacy of these herbs for gas gangrene requires further confirmation.
3% hydrogen peroxide or 1:1000 potassium permanganate solution (both are an oxidizing agent and antiseptic) (Appendix 1) can be used to clean the wound site repeatedly, which may help the disinfection and the improvement of hypoxic condition (Chen 2011).
Animal studies have shown that ozone (oxygen molecules with three atoms, rather than the normal two), which inactivates most bacterial species, may have some effect on treating gas gangrene (Rotter 1974; Stanek 1976), but further research is needed to verify these findings.
Antitoxin, an antibody with the ability to neutralize a specific toxin, has been used to alleviate the poisoning symptoms, but was not recommended because of its risk of increasing hypersensitivity (undesirable reactions caused by the immune system) (Appendix 1) (Schwartz 1978).
Why it is important to do this review
Gas gangrene is a severe condition with a high fatality rate. Although it occurs less frequently than other wound infections, when it does occur, delay in diagnosis and treatment, or inadequate deployment of interventions may result in amputation, permanent disability or even death. Resolute and effective measures are needed to ensure favourable prognoses in people with gas gangrene. This review is intended to summarize current best evidence of the efficacy of interventions for treating gas gangrene, and to highlight gaps in the relevant research.