AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Clostridial gas gangrene is a highly lethal necrotizing soft tissue infection of skeletal muscle caused by toxin- and gas-producing Clostridium species. The synonym clostridial myonecrosis better describes both the causative agent and the target tissue. Prior to the advent of antibiotics and mobile army surgical hospitals, as many as 5% of battlefield injuries were complicated by this condition. However, the incidence rate dropped to less than 0.01% during the Vietnam War. Presently, 90% of contaminated wounds demonstrate clostridial organisms, but fewer than 2% develop clostridial myonecrosis. This underscores the importance of host and local wound factors in the development of this process, rather than the mere presence of the organisms in the wound.

Pathophysiology

Clostridia are gram-positive, anaerobic, spore-forming bacilli commonly found throughout nature (with the exception of the North African desert). Cultivated rich soil has the highest density of organisms. In addition, clostridia have been isolated from normal human colonic flora, skin, and the vagina. More than 150 Clostridium species have been identified, but only 6 have been demonstrated to be capable of producing the fulminant condition known as clostridial gas gangrene. Usually, more than 1 species is isolated from clinical specimens.

Clostridium perfringens, previously known as Clostridium welchii, is the most common cause of clostridial gas gangrene and is present in 80-90% of cases. Other clostridia species may include Clostridium novyi (40%), Clostridium septicum (20%), Clostridium histolyticum (10%), Clostridium bifermentans (10%), and Clostridium fallax (5%).

Infections are characterized by a very low level of host inflammation in response to organism-associated exotoxins. In fact, it is more of a response to the exotoxins than a classic immune response to invading organisms. Purulence often is absent. The process of myonecrosis can spread as fast as 2 cm/h. This results in systemic toxicity and shock that can be fatal within 12 hours. Overwhelming shock with accompanying renal failure usually leads to patient death.

Infection requires 2 conditions to coexist. First, organisms must be inoculated into the tissues. Second, oxygen tension must be low enough for the organisms to proliferate. These organisms are not strict anaerobes; 30% oxygen tension in the tissues allows for free growth of these bacteria, but 70% oxygen tension restricts their growth. Inoculation of organisms into low oxygen tension tissues is followed by an incubation period that usually ranges from 12-24 hours. However, this period can be as brief as 1 hour or as long as several weeks. The organisms then multiply and produce exotoxins that result in myonecrosis.

Although not very well understood, exotoxins appear to be tissue-destructive soluble antigens produced by clostridia. They include lecithinase, collagenase, hyaluronidase, fibrinolysin, hemagglutinin, and hemolysin toxins. C perfringens produces at least 17 identifiable exotoxins that are used for species typing (eg, type A, type B, type C).

Theta toxin causes direct vascular injury, cytolysis, hemolysis, leukocyte degeneration, and polymorphonuclear cell destruction. These effects on leukocytes may explain the relatively minor host inflammatory response that is observed in tissues of patients with clostridial myonecrosis.

Kappa toxin, also produced by C perfringens, is a collagenase that facilitates the rapid spread of necrosis through tissue planes by destroying connective tissue.

Alpha toxin is produced by most clostridia and has phospholipase C activity. This potent lecithinase causes lysis of red blood cells, myocytes, fibroblasts, platelets, and leukocytes. It also may decrease cardiac inotropy and trigger histamine release, platelet aggregation, and thrombus formation.

Frequency

United States

Approximately 1000 cases occur per year.

International

Although no published data exist, prevalence is most likely higher than in the United States because of lack of access to health care in other parts of the world.

Mortality/Morbidity

If properly treated, the overall mortality rate is 20-30%. If untreated, the process is 100% fatal.

• Spontaneous cases have a mortality rate of 67-100%.
• With trunk involvement, the mortality rate is higher (60%) than the mortality rate associated with involvement of the extremities, which has a better prognosis.
• A longer incubation period, presence of significant comorbidities, and development of shock increase the mortality rate.

Race

No race predilection exists.

Sex

No sex predilection exists.

Age

Age does not seem to be an independent risk factor. However, because significant comorbidities are present more often among patients who are elderly, they have a higher overall mortality rate than younger patients.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Obtaining a thorough medical history is important. It helps the physician identify risk factors that may affect the progression of the disease and the prognosis.

• Pain
• • Increasing pain after surgery or trauma
  • Out of proportion to physical findings
  • Sudden onset
  • May be quite severe
• Prior trauma
• Prior surgery, including abortions
• Diabetes mellitus
• Peripheral vascular disease
• Alcoholism
• Drug abuse
• Age
• Chronic debilitating disease(s)
• Immunocompromised state
• • Steroid use
  • Malnutrition
  • Malignancy
  • Acquired immunodeficiency syndrome (AIDS)

Physical

Perform a thorough physical examination before focusing on the involved body part.

• Vital signs - May indicate systemic toxicity and include no or low-grade fever, tachycardia (relative tachycardia), tachypnea, hypotension, or hypoxia
• Edema bullae
• Erythema with purplish black discoloration
• Extreme tenderness
• Brownish skin discoloration (bronzing, brawny) with bullae
• Profuse, "dish-watery," serous drainage from ruptured bullae
• Discharge - May have a peculiar, "mousy," sweet odor
• Minimal crepitant bullae
• Crepitant tissue - May extend well beyond any skin discoloration, edema, or bleb formation
• Mental status - Paradoxically, may be depressed early during the disease course; sensorium then may clear as the disease progresses and the patient is near death

Causes

The disease process must include tissue inoculation and a low oxygen tension environment. More than 50% of cases are preceded by trauma. Other cases occur spontaneously or in patients after operative procedures.

• Trauma
• • Compound fractures
  • Foreign bodies
  • Frostbite
  • Thermal or electrical burns
  • Subcutaneous or intravenous injection of medications or illicit drugs
  • Pressure sores
  • Motor vehicle crashes
• Postoperative
• • Gastrointestinal tract surgery
  • Genitourinary tract surgery
  • Abortion
  • Amputation
  • Tourniquets, casts, bandages, or dressings applied too tightly
• Spontaneous
• • This also is known as nontraumatic, idiopathic, or metastatic gas gangrene.
  • It most often is mixed infection caused by C septicum, C perfringens, and C novyi. Several series report a mortality rate that approaches 100%.
  • The gastrointestinal tract is the source of organisms. The organisms escape the bowel by translocation, enter the bloodstream, and seed distant sites where they can cause gas gangrene. This process also may result in a more localized infection that involves the viscera or intra-abdominal compartment.
  • Approximately 80% of nontrauma patients have an overt or occult malignancy. Of these, approximately 40% are hematologic malignancies and an additional 34% are colorectal. Survival from this process should initiate a search for an occult malignancy if none has been documented previously in nontrauma patients.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Anaerobic (nonclostridial) cellulitis and/or myositis
Bacterial synergistic gangrene
Nonclostridial necrotizing fasciitis
Nonclostridial infections involving muscle (Peptostreptococcus species, Streptococcus pyogenes, Staphylococcus aureus, Vibrio vulnificus)
Pyomyositis
Rhabdomyolysis
Synergistic necrotizing cellulitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• White blood cell count may be normal or elevated. Immature forms usually are increased.
• Elevated liver function test results may indicate progressive hepatic dysfunction.
• Elevated blood urea nitrogen and creatinine may indicate azotemia, renal insufficiency, or renal failure.
• Myonecrosis may elevate serum aldolase, potassium, lactate dehydrogenase, and creatine phosphokinase levels.
• Profound anemia may result from severe intravascular hemolysis.
• Arterial blood gas determinations and chemistry panel analysis may reveal metabolic acidosis.
• Disseminated intravascular coagulation may result from exotoxin release.
• A Gram stain of the wound discharge reveals gram-positive rods and an absence of polymorphonuclear cells. Other organisms also may be present in as many as 75% of cases. This test is essential for rapid diagnosis.
• An assay for sialidases (neuraminidase) produced by clostridia also may be performed on serum and wound discharge. These tests provide rapid (<2 h) confirmation of Gram stain results.

Imaging Studies

• Radiographs reveal fine gas bubbles within the soft tissues, dissecting into the intramuscular fascial planes and muscles. Other necrotizing soft tissue infections produce abundant gas, in contrast to the paucity of gas of clostridial gas gangrene.
• Intra-abdominal clostridial gas gangrene is evaluated most readily by a computed tomography scan that demonstrates extraluminal gas.

Other Tests

• Blood and bullous fluid cultures reveal clostridia but take at least 48 hours to perform. They are not useful because the delay almost certainly results in death.

Histologic Findings

Histologic analysis reveals necrotic muscle, clostridia, and a minimal inflammatory infiltrate.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Successful therapy requires rapid diagnosis and aggressive early treatment. The physician must maintain a high index of suspicion for this uncommon but potentially fatal process. Consider any patient in whom clostridial gas gangrene is suspected critically ill.

• Obtain an early surgical consultation for debridement.
• Administer supplemental oxygen.
• Restore intravenous fluid volume and monitor urine output with an indwelling bladder catheter.
• Transfer to an intensive care unit that has telemetry and pulse oximetry.
• Make sure tetanus immunity is adequate.
• Consider hyperbaric oxygen therapy.
• • Clostridia lack superoxide dismutase, making them incapable of surviving in the oxygen-rich environment created within a hyperbaric chamber. This inhibits clostridial growth, exotoxin production, and exotoxin binding to host tissues.
  • Hyperbaric oxygen therapy also may promote host polymorphonuclear cell function.
  • Animal studies clearly have demonstrated a survival advantage when this therapy is combined with antibiotics and debridement. However, no randomized controlled studies of humans exist to support this finding.
  • Hyperbaric oxygen should be used at the discretion of the treating physician but should never cause a delay in surgical debridement. Transporting a patient from one facility to another merely to administer hyperbaric oxygen probably is not warranted and may be detrimental.
  • Administer therapy 3 times a day for 2 days, then twice a day for several more days, until the disease process is well under control.
  • The dose is usually 2.5 atmospheres absolute (ATA) oxygen for 120 minutes or 3 ATA oxygen for 90 minutes. The pressure at sea level equals 1 ATA.
  • Complications include fire, seizures, decompression sickness, middle ear barotrauma, and claustrophobia.
  • The only absolute contraindication is the presence of an untreated pneumothorax.

Surgical Care

Clostridial gas gangrene represents a true surgical emergency.

• It requires prompt aggressive debridement of all involved tissues.
• Extensive extremity involvement may require amputation.
• Because the disease process may continue to involve additional tissue, daily exploration and further debridement may be necessary.
• Wound exploration reveals gas, watery discharge, and necrotic muscle. Muscle tissue may be pale, edematous, and may not bleed when cut or contract when stimulated with electricity.
• If the patient survives, the wound may be closed at a later date or allowed to heal secondarily (by wound contraction and spontaneous reepithelialization).

Consultations

• Infectious disease specialists
• General, trauma, or burn surgeon
• Plastic surgeon

Diet

• Ensure that the patient receives adequate nutritional support during this period of increased energy requirements.
• During the period of critical illness, administration of enteral or parenteral nutrition may be required.
• Consultation with a nutritionist ensures optimal nutritional replacement.
• Frequently monitor nutritional status through serum markers and nitrogen balance determination.

Activity

• Once patients have survived the critical period of illness, they may benefit from occupational or physical therapy to restore preinjury function.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Antibiotics

Penicillin is the preferred drug for clostridial infections. Patients allergic to penicillin may be treated with clindamycin or chloramphenicol.

Drug Name	Clindamycin (Cleocin)
Description	Lincosamide for treatment of serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose	600 mg IV divided q8h
Pediatric Dose	20 mg/kg IV divided q8h
Contraindications	Documented hypersensitivity; regional enteritis; ulcerative colitis; severe hepatic impairment; antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis

Drug Name	Chloramphenicol (Chloromycetin)
Description	Effective against many gram-positive and gram-negative bacteria, including clostridia. Inhibits growth by binding to 50S ribosomal subunit.
Adult Dose	500-1000 mg IV q6h
Pediatric Dose	50-75 mg/kg/d IV divided q6h
Contraindications	Documented hypersensitivity
Interactions	Concurrently with barbiturates, serum levels may decrease while barbiturate levels may increase, causing toxicity; manifestations of hypoglycemia may occur with sulfonylureas; rifampin may reduce serum levels, presumably through hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity (chloramphenicol levels may be increased or decreased)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use only for indicated infections; serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; evaluate baseline and perform periodic blood studies approximately every 2 d while in therapy; discontinue upon appearance of leukopenia, thrombocytopenia, anemia, or findings attributable to chloramphenicol; adjust dose in severe liver dysfunction

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• If patients survive, they typically are hospitalized for several weeks.

Transfer

• Transfer is required infrequently and may be detrimental to the patient.
• As long as the treating facility has the capability and experience to provide adequate surgical and intensive care, no transfer is necessary.
• Transfer merely to obtain access to hyperbaric oxygen therapy is not indicated.

Complications

• Death
• Amputation
• Permanent deformity or disability

Prognosis

• Most patients do fairly well if they survive the initial critical period.
• Shock in patients presenting with clostridial myonecrosis portends a worse prognosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to make a correct and timely diagnosis of clostridial gas gangrene can lead to catastrophic, if not life-threatening, consequences for the patient.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Burke MP, Opeskin K. Nontraumatic clostridial myonecrosis. Am J Forensic Med Pathol. Jun 1999;20(2):158-62. [Medline].
• Ellemor DM, Baird RN, Awad MM, et al. Use of genetically manipulated strains of Clostridium perfringens reveals that both alpha-toxin and theta-toxin are required for vascular leukostasis to occur in experimental gas gangrene. Infect Immun. Sep 1999;67(9):4902-7. [Medline].
• Feingold DS. Gangrenous and crepitant cellulitis. J Am Acad Dermatol. Mar 1982;6(3):289-99. [Medline].
• Hart GB, Lamb RC, Strauss MB. Gas gangrene. J Trauma. Nov 1983;23(11):991-1000. [Medline].
• Hatheway CL. Toxigenic clostridia. Clin Microbiol Rev. Jan 1990;3(1):66-98. [Medline].
• Hirn M. Hyperbaric oxygen in the treatment of gas gangrene and perineal necrotizing fasciitis. A clinical and experimental study. Eur J Surg Suppl. 1993;1-36. [Medline].
• Korhonen K, Klossner J, Hirn M, Niinikoski J. Management of clostridial gas gangrene and the role of hyperbaric oxygen. Ann Chir Gynaecol. 1999;88(2):139-42. [Medline].
• Larson CM, Bubrick MP, Jacobs DM, West MA. Malignancy, mortality, and medicosurgical management of Clostridium septicum infection. Surgery. Oct 1995;118(4):592-7; discussion 597-8. [Medline].
• McDonel JL. Clostridium perfringens toxins (type A, B, C, D, E). Pharmacol Ther. 1980;10(3):617-55. [Medline].
• Present DA, Meislin R, Shaffer B. Gas gangrene. A review. Orthop Rev. Apr 1990;19(4):333-41. [Medline].
• Rood JI, Cole ST. Molecular genetics and pathogenesis of Clostridium perfringens. Microbiol Rev. Dec 1991;55(4):621-48. [Medline].
• Samlaska CP, Maggio KL. Subcutaneous emphysema. Adv Dermatol. 1996;11:117-51; discussion 152. [Medline].
• Stephens MB. Gas gangrene: potential for hyperbaric oxygen therapy. Postgrad Med. Apr 1996;99(4):217-20, 224. [Medline].
• Stevens DL, Tweten RK, Awad MM, et al. Clostridial gas gangrene: evidence that alpha and theta toxins differentially modulate the immune response and induce acute tissue necrosis. J Infect Dis. Jul 1997;176(1):189-95. [Medline].
• Valentine EG. Nontraumatic gas gangrene. Ann Emerg Med. Jul 1997;30(1):109-11. [Medline].
• Weinstein L, Barza MA. Gas gangrene. N Engl J Med. Nov 22 1973;289(21):1129-31. [Medline].

Article Last Updated: Feb 15, 2006