Intervention Protocol

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Interventions for treating gas gangrene

  1. Zhirong Yang1,
  2. Jing Hu1,
  3. Yanji Qu1,
  4. Feng Sun1,
  5. Xisheng Leng2,
  6. Hang Li3,
  7. Siyan Zhan1,*

Editorial Group: Cochrane Wounds Group

Published Online: 6 JUN 2013

DOI: 10.1002/14651858.CD010577


How to Cite

Yang Z, Hu J, Qu Y, Sun F, Leng X, Li H, Zhan S. Interventions for treating gas gangrene (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD010577. DOI: 10.1002/14651858.CD010577.

Author Information

  1. 1

    School of Public Health, Peking University, Centre for Evidence Based Medicine and Clinical Research, Department of Epidemiology and Biostatistics, Beijing, China

  2. 2

    Peking University People's Hospital, Department of Surgery, Beijing, Xicheng District, China

  3. 3

    Peking University First Hospital, Dermatologic Department, Beijing, Xicheng District, China

*Siyan Zhan, Centre for Evidence Based Medicine and Clinical Research, Department of Epidemiology and Biostatistics, School of Public Health, Peking University, 38 Xueyuan Road, Haidian District, Beijing, 100191, China. siyan-zhan@bjmu.edu.cn.

Publication History

  1. Publication Status: New
  2. Published Online: 6 JUN 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Description of the condition

 

Gas gangrene

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).

 

Epidemiology

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.

 

Diagnosis

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

 

Immediate debridement

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).

 

Antibiotic treatment

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).

 

Additional therapy

 

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.

 

Others

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.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

The primary objective of this review is to determine the effect of all potential interventions for treating gas gangrene infections on outcomes including amputation rates, infection-related fatality rates and quality of life.

The secondary objective of this review is to assess the effect of all potential interventions for gas gangrene infections on all-cause fatality, cure rate within a specified period of time, time to complete healing within the trial period, and severe adverse events or complications.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

We will include randomised controlled trials (RCTs) in which people, rather than limbs or wounds, were randomly allocated into different treatments. In the absence of RCTs, we will consider quasi-randomised controlled trials (qRCTs), the level of evidence of which is considered secondary to RCTs in terms of the evaluation of efficacy. We will exclude any other type of study.

 

Types of participants

We will include studies involving people with gas gangrene irrespective of age, gender, etiology and severity. A diagnosis of gas gangrene will depend on a history of serious trauma or surgery, and clinical presentation, including wounds with unusual swelling and pain, and symptoms of systemic poisoning. Anaerobic bacterial culture and tissue biopsy will be considered as the gold standard for diagnosis. Different study authors' definitions of gas gangrene will be also accepted, but considered critically.

 

Types of interventions

In this review, we will consider all types of interventions for the treatment of gas gangrene. Interventions of interest will include (but not be limited to) surgical debridement, antibiotic treatment, hyperbaric oxygen (HBO) therapy, Chinese herbal medicines, systemic support therapy, wound irrigation, ozone and antitoxin. We will include studies that:

  • compare one regimen or treatment with another regimen, treatment or with no treatment.

 

Types of outcome measures

We will analyse end of treatment outcomes, and also change between beginning and end of treatment outcomes, where applicable.

 

Primary outcomes

  1. Amputation due to gas gangrene.
  2. Infection-related fatality attributed to gas gangrene.
  3. Quality of life: measured by a standardised generic questionnaire such as EQ-5D, SF-36, or SF-6, or SF-12.

 

Secondary outcomes

  1. All-cause fatality.
  2. Cure rate in a specified period of time (at a patient level).
  3. Time to complete healing during the trial period (at a patient level).
  4. Severe adverse events or complications including, but not limited to: anaphylaxis (allergic reaction that may cause death), liver injury, gastrointestinal symptoms (caused by antibiotics), oxygen toxicity, barotrauma, decompression sickness, pulmonary damage (caused by HBO therapy), shock, renal failure and multiple organ dysfunction syndrome.

 

Search methods for identification of studies

 

Electronic searches

We will search the following electronic databases to identify reports of relevant randomised clinical trials:

  • The Cochrane Wounds Group Specialized Register;
  • The Cochrane Injuries Group Specialized Register;
  • The Cochrane Central Register of Controlled Trials (CENTRAL) (latest issue), part of The Cochrane Library. www.thecochranelibrary.com;
  • OVID MEDLINE (January 1946 to present);
  • EMBASE (January 1974 to present);
  • EBSCO CINAHL (1982 to present);
  • Science Citation Index (1981 to present);
  • China Biological Medicine Database (CBM-disc) (1979 to present);
  • China National Knowledge Infrastructure (CNKI) (1979 to present);
  • Chinese scientific periodical database of VIP INFORMATION (VIP) (1989 to present).

We will use the following provisional search strategy in The Cochrane Central Register of Controlled Trials (CENTRAL):

#1 MeSH descriptor Gas Gangrene explode all trees
#2 gas* NEXT gangrene:ti,ab,kw
#3 clostridi* NEXT myonecrosis:ti,ab,kw
#4 ((nonclostridi* OR non-clostridi*) NEXT myonecrosis):ti,ab,kw
#5 (#1 OR #2 OR #3 OR #4)

We will search the following clinical trials registries:

  • ClinicalTrials,gov (www.clinicaltrials.gov)
  • Current Controlled Trials (www.controlled-trials.com)
  • WHO International Clinical Trials Registry Platform (www.who.int/trialsearch)
  • Australian New Zealand Clinical Trials Registry (www.anzctr.org.au)

No study design filters will be used, and we will not restrict studies with respect to language, date of publication or study setting. The proposed CENTRAL strategy will be adapted to search the other electronic databases where appropriate.

 

Searching other resources

 

Handsearching

We will try to identify additional studies by searching the reference lists of all relevant trials and reviews we identify.

 

Other search strategies

We will contact authors of related identified studies to obtain missing data that were not reported in the original trials, additional references, unpublished and ongoing trials.

 

Data collection and analysis

 

Selection of studies

Independently, two review authors (ZY, JH) will undertake examination of all references retrieved by the search, and select trials meeting the inclusion criteria. Any disagreements will be resolved by discussion between the review authors, with adjudication by the third review author (YQ).

 

Data extraction and management

Independently, two review authors (ZY, YQ) will extract data concerning details of study population (age, gender, setting, severity, pathogen), characteristics of the study, nature of the interventions and outcomes, using a pre-designed data extraction form. We will try to contact the authors of the original studies to obtain more information, particularly in the case of missing or unclear data. if we identify differences in data extraction, we will refer back to the original articles and discuss the differences. Any disagreements will be resolved by consensus.

 

Assessment of risk of bias in included studies

Independently, two review authors (ZY, YQ) will perform methodological quality assessment using the Cochrane Collaboration tool for assessing risk of bias (Higgins 2011). If necessary, we will resolve any disagreement through discussion with a third review author (SZ).

The Cochrane Collaboration tool for assessing risk of bias includes seven specific domains, namely:

  1. random sequence generation;
  2. allocation concealment;
  3. blinding of participants and personnel;
  4. blinding of outcome assessment;
  5. incomplete outcome data;
  6. selective outcome reporting;
  7. other sources of bias.

We will also evaluate other characteristics of included studies such as: explicit diagnostic criteria, explicit inclusion criteria, explicit outcome measures, completeness of follow-up, method of randomisation, and whether any imbalances in prognostically-important variables has been taken into account.

Each criterion will be judged as being: 'low' (meaning low risk of bias), 'high' (high risk of bias) or 'unclear' (lack of information or uncertainty about the risk of bias). Assessment of risk of bias will be presented using a 'Risk of bias summary figure' to display the quality of all included studies.

 

Measures of treatment effect

We will report the quantitative data in individual trials for outcomes listed in the inclusion criteria using risk ratio (RR) with corresponding 95% confidence interval (CI) for dichotomous outcomes, standardised mean difference (SMD) with 95% CI for continuous outcomes (e.g. quality of life), and hazard ratio (HR) and 95% CI for time-to-event outcomes (e.g. time to healing).

 

Unit of analysis issues

The unit of analysis for all the outcomes in our review will be the individual person rather than a limb or a wound. We will exclude studies in which an individual might receive different treatments to different limbs or wounds simultaneously. For studies where the limb or the wound was used as the unit of analysis, we will first contact the authors in attempt to confirm whether an individual received only one treatment. If so, we will ask for the data at the individual level; otherwise, we will exclude these studies. In case we fail to attain such data, we will treat it as missing data and undertake a sensitivity analysis where we assume the worst outcome for participants who have data missing.

 

Dealing with missing data

Where appropriate, we will try to contact the authors of included trials to obtain missing data. For time-to-event outcomes, if the authors did not report HR and 95% CI in the primary studies, we will ask them to provide individual patient data, or will report the results narratively. If missing data cannot be obtained from the study authors, we will analyse the data that are available, and then perform sensitivity analyses where we assume the worst outcome for participants who have been lost to follow-up.

 

Assessment of heterogeneity

We will assess the studies for clinical heterogeneity by checking the inclusion criteria, exclusion criteria, differences in the intervention, differences in the control and differences in the way outcomes were defined. We will also assess methodological heterogeneity by examining the risk of bias of any included trial. In addition, statistical heterogeneity will be considered and calculated by the Q statistic and I² values. We will interpret I² statistic values of more than 50%, or a P value of less than 0.10, as representing substantial heterogeneity.

 

Assessment of reporting biases

If there are sufficient studies available, we will assess publication bias by means of a funnel plot. If there is evidence of asymmetry after statistical assessment, publication bias will be considered to be one of the possible explanations.

 

Data synthesis

We will conduct a head-to-head comparison across trials using the statistical package within the Cochrane review-writing software, Review Manager (RevMan). Results will be expressed as RR with 95% CI for dichotomous outcome measures, SMD with 95% CI for continuous outcomes such as quality of life, where different assessment scales may be used in different studies, and HR with 95% CI for time-to-event outcomes. We will use a fixed-effect model unless there is evidence of heterogeneity (I² over 25%) suggesting that a random-effects model would be more appropriate. For time-to-event data, we plan to use the inverse variance method on the estimated HR and standard error. When there is high statistical heterogeneity (I² over 50%), we will not pool the results but present them in a narrative format.

 

Subgroup analysis and investigation of heterogeneity

In the presence of sufficient studies, analyses will be conducted separately to study the difference in results for the following groups:

  1. etiologies: post-traumatic, post-operative and spontaneous;
  2. location of gas gangrene: extremity versus trunk;
  3. patient age: children (ages between 0 and 18 years) compared with adults (over 18 years).

 

Sensitivity analysis

In the presence of a sufficient number of studies, we will do a sensitivity analysis to investigate whether and how results may be affected if studies with missing data or without adequate allocation concealment, blinding, or a clearly specified definition of gas gangrene are excluded from the analyses.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Many thanks to Sally Bell-Syer, the Managing Editor of the Cochrane Wounds Group, for providing us with useful suggestions when we encountered difficulties during development of the protocol. Many thanks also to Trials Search Co-ordinator, Ruth Foxlee, for helping us revise the search strategy. Many thanks also to other members of the Cochrane Wounds Group who contributed to our protocol, the peer referees (Mark Rodgers, Marialena Trivella, Dirk Ubbink, Uwe Wollina, Durhane Wong Rieger) and copy editor Elizabeth Royle.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. Glossary

Serosanguinous exudate: the liquid that drains from open wounds in the human body. Exudate is made up of the serum around inflamed and damaged tissue. One type of exudate, called serosanguinous exudate, appears pink due to a small number of blood cells mixing with the fluid that is draining out.

Exotoxins: potent toxins secreted by micro-organisms and released into their surroundings. These can cause damage to people by destroying cells or disrupting normal cellular metabolism. Exotoxins are proteins and so can be destroyed by heat, or detoxified by treatment with formaldehyde. Bacteria of the genus Clostridium are one of the most frequent producers of exotoxins.

Necrosis: the death of cells or tissues from severe injury or disease, especially in a localized area of the body. Causes of necrosis include inadequate blood supply (as in infarcted tissue), bacterial infection, traumatic injury, and hyperthermia (being too hot).

Haematogenous spread: the term given to the dissemination of Clostridium through the blood stream, usually to an extremity or abdominal wall, causing necrotizing infection.

Haemorrhagic bulla: a fluid-containing, elevated lesion of the skin, usually more than 5 mm in diameter and characterized by subcutaneous and mucosal haemorrhage, with a very clear boundary.

Malodour: the smell that accompanies gangrene is a distinctive odour that is offensively unpleasant.

Crepitus: a sound or feeling that resembles the crackling noise heard when rubbing hair between the fingers or throwing salt on an open fire. Crepitus is associated with gas gangrene, and is caused by rubbing of bone fragments, air in superficial tissues, and the crackles of a consolidated area of the lung in pneumonia.

Debridement: surgical removal of foreign material and dead tissue from a wound in order to promote healing and prevent infection.

Myositis: inflammation of a muscle, especially a voluntary muscle, characterized by pain, tenderness, and sometimes spasm in the affected area.

Barotrauma: physical damage to body tissues caused by a difference in pressure between an air space inside or beside the body and the surrounding fluid. Damage occurs in the tissues around the body's air spaces because gases are compressible and the tissues are not. During increases in ambient pressure, the internal air space provides the surrounding tissues with little support to resist the higher external pressure. During decreases in ambient pressure, the higher pressure of gas inside air spaces causes damage to the surrounding tissues if that gas becomes trapped.

Clostridial bacteremia: the presence of clostridial bacteria in the blood. Since the blood is normally a sterile environment, the detection of bacteria in the blood (most commonly with blood cultures) is always abnormal.

Central venous pressure: the venous pressure as measured at the right atrium, done by means of a catheter introduced through the median cubital vein to the superior vena cava.

Pulmonary capillary wedge pressure: an indirect indication of left atrial pressure obtained by wedging a catheter into a small pulmonary artery tightly enough to block flow from behind and thus to sample the pressure beyond.

Packed cell volume: the ratio of the volume occupied by packed red blood cells to the volume of the whole blood.

Detumescence: diminution of swelling or the subsidence of anything swollen.

Antitoxin: antibody produced in response to a toxin of bacterial, animal, or plant origin (the origin in this text refers to the clostridial bacteria causing gas gangrene) with the ability to neutralize the effects of the toxin.

Hydrogen peroxide: an oxidizing and unstable compound of hydrogen and oxygen that is easily broken down into water and oxygen. A 3% solution is used as a mild antiseptic for the skin and mucous membranes; more concentrated solutions may be used as a bleaching agent.

Potassium permanganate: a dark purple crystalline compound used as an oxidizing agent and disinfectant in medicine.

Hypersensitivity: a state of altered reactivity in which the body reacts with an exaggerated immune response to what is perceived as a foreign substance.

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Zhirong Yang identified references for the background section; designed and drafted the protocol; and will be responsible for selecting studies, extracting data, interpreting analysis and review development.
Jing Hu supported development of the protocol from a methodological aspect, and will be in charge of study selection and data extraction.
Xisheng Leng and Hang Li serve as our clinical experts and will co-author the review.
Yanji Qu contributed to the methods section and will be involved in studies selection and extracting of data.
Feng Sun contributed to the statistical sections and will be responsible for statistical analysis and interpretation.
Siyan Zhan gave effective guidance and revised the protocol and will be responsible for review development.

 

Contributions of editorial base:

Nicky Cullum: edited the protocol; advised on methodology, interpretation and protocol content.
Joan Webster, Editor: Approved the final protocol prior to submission.
Sally Bell-Syer: coordinated the editorial process. Advised on methodology, interpretation and content. Edited the protocol.
Ruth Foxlee: designed the search strategy and edited the search methods section.
Rachel Richardson: edited the protocol

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • Peking University Health Science Centre, China.

 

External sources

  • NIHR/Department of Health (England), (Cochrane Wounds Group), UK.

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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