Gas Gangrene

Background: Gas gangrene, a subset of necrotizing myositis, is an infectious disease emergency caused by organisms in the Clostridium species. The hallmarks of this disease are rapid onset of myonecrosis, gas production, and sepsis.

Pathophysiology: Bacteria in the Clostridium species are gram-positive, spore-forming, anaerobic rods normally found in soil and the gastrointestinal tract of humans and animals. They most often cause disease in the setting of trauma or surgery but can also occur spontaneously in the absence of definite risk factors or exposures. Not all wounds contaminated with clostridia develop gas gangrene; the myonecrosis seems to only develop when sufficient devitalized tissue is present to support anaerobic metabolism.

Traumatic and surgical gas gangrene occurs through direct inoculation of a wound. With a compromised blood supply, the wound has an anaerobic environment that is ideal for Clostridium perfringens, the cause of 80-95% of cases of gas gangrene.

Spontaneous gas gangrene is most often caused by hematogenous spread of Clostridium septicum from the gastrointestinal tract in patients with colon cancer. The organism enters the blood via a small break in the gastrointestinal mucosa and subsequently seeds muscle tissue. Unlike C perfringens, C septicum is aerotolerant and can infect normal tissues.

In both traumatic gas gangrene and spontaneous gas gangrene, exotoxin, not bacterial proliferation, is responsible for the rapid progression of infection. Exotoxin hydrolyses cell membranes, causes tissue necrosis by inducing occlusive microvascular thrombosis, and has direct cardiodepressive effects. Products of tissue breakdown, including creatine phosphokinase, myoglobin, and potassium, cause secondary toxicity.

Frequency:

• In the US: Estimates of incidence of gas gangrene vary; however, cases are relatively rare. Data from 1975 estimate 900-1000 cases per year, or 0.03-5.2% of open wounds, depending on type of wound and treatment.

• Internationally: No data are published, but incidence is probably higher than in the United States. Incidence is highest in areas with poor access to proper wound care.

Mortality/Morbidity:

• Mortality from traumatic gas gangrene is greater than 25%.

• Mortality from nontraumatic gas gangrene caused by C septicum ranges from 67-100%.

Age:

• Occurrence is not age specific.

• Diabetic peripheral vascular disease and other chronic immunocompromised states that can predispose individuals to gas gangrene are more prevalent in older populations.

• The incubation period is usually less than 24 hours but ranges from 6 hours to several days.

• Pain is often out of proportion to physical findings. This clinical finding reflects the hypoxic state of the muscle tissue and is a key to distinguishing gas gangrene from simple cellulitis.

• Decreased pain or anesthesia at the site of infection can indicate that cutaneous nerve endings are being destroyed and that the disease is advanced.

• Progression to toxemia and shock can be rapid.

Physical:

• Local findings

• Because gas gangrene affects the deep muscle tissue, the superficial skin often appears normal early in the disease course but eventually turns pale and then to a grey or purplish red color.

• Crepitance or subcutaneous air

• Tense edema

• Discolored wound discharge

• Vesicles or bullae

• Necrotic tissue

• Systemic findings

• Fever, often low grade early in the disease

• Tachycardia

• Altered mental status

• Diaphoresis

Causes:

• Risk factors

• Atherosclerosis

• Burns

• Chronic alcoholism

• Corticosteroid use

• Diabetes

• Gastrointestinal malignancy

• Hypoalbuminemia

• Intravenous drug abuse

• Malnutrition

• Obesity

• Peripheral vascular disease

• Surgery

• Trauma

Other causes of necrotizing myositis (group A streptococci, polymicrobial aerobic-anaerobic flora, and nonclostridial anaerobes)
Cutaneous anthrax
Vaccinia vaccination
Acute gout
Septic arthritis
Familial Mediterranean fever
Fixed drug reaction
Pyoderma gangrenosa
Sweet syndrome
Wells syndrome
Carcinoma erysipeloides
Pyomyositis
Water-borne skin infections (Vibrio vulnificus, Aeromonas hydrophila, Mycobacterium marinum)
Other causes of soft tissue gas (eg, pneumomediastinum, pneumothorax, fractured larynx, fractured trachea)

Lab Studies:

• Gram stain and culture of bullae fluid: If clostridial species are present, a Gram stain may demonstrate gram-positive rods. While this information can be helpful, simple superficial wound swabs should not be obtained. Microorganisms that colonize the skin surface often do not contribute to the underlying infection.

• Complete blood count: CBC may reveal evidence of hemolysis and anemia secondary to release of toxins.

• Liver function tests: Hyperbilirubinemia and liver dysfunction may result from release of toxins.

• Electrolytes: Hyperkalemia can result from cell breakdown. Hypocalcemia may result from subcutaneous fat necrosis.

• Renal panel: Kidney dysfunction may occur secondary to hypotension, hemoglobinuria, and myoglobinuria.

• Arterial blood gas: Gas gangrene can cause metabolic acidosis.

• Coagulation panel: Coagulopathy and thrombocytopenia can result.

• Myoglobin: Myoglobinemia and myoglobinuria can result from cellular breakdown.

• Blood cultures: This may help narrow antibiotic coverage.

Imaging Studies:

• Gas in the soft tissues is neither sensitive nor specific for gas gangrene. Many different bacteria, trauma, and visceral perforation can cause soft tissue gas. However, plain radiographs or ultrasonography can be used to look for the presence of gas.

• Computed tomography or magnetic resonance imaging can help to evaluate the depth of soft tissue inflammation.

Procedures:

• Tissue biopsy is the criterion standard in helping make the diagnosis of gas gangren

Prehospital Care:

• Oxygenation

• Intravenous (IV) fluids

Emergency Department Care:

• Continue managing the airway and breathing of the patient.

• Frequent assessment of the circulatory status is necessary.

• Use vasoconstrictors only if absolutely necessary; they can decrease perfusion to already ischemic tissue.

• Administer tetanus toxoid if indicated.

• Administer antibiotics.

• Correct electrolyte abnormalities.

• Check compartment pressures if severe pain and evidence of compartment syndrome are present with minimal cutaneous evidence of infection.

Consultations:

• Surgery

• Obtain immediate surgical consultation.

• Definitive treatment of gas gangrene is wide debridement of necrotic muscle. This is identifiable because it does not bleed or contract when debrided.

• While laboratory studies and imaging studies may help make the diagnosis of gas gangrene, the criterion standard is tissue biopsy.

Antibiotics may not penetrate the ischemic muscle but are important adjuncts to surgery.

Drug Category: Antibiotics -- Clostridial species are exquisitely sensitive to a combination of penicillin G and clindamycin. However, because it is difficult initially to distinguish gas gangrene from other soft tissue infections, such as necrotizing fasciitis, which is caused by a broad spectrum of pathogens, empiric first-line antibiotic therapy should be broad.

Antibiotic treatment should include gram-positive (penicillin or cephalosporin), gram-negative (aminoglycoside, third-generation cephalosporin, or ciprofloxacin), and anaerobic coverage (clindamycin or metronidazole). In addition, vancomycin or linezolid should be considered in those at risk for methicillin resistant Staphylococcus aureus (MRSA). In some communities MRSA infections are now being isolated even in those without risk factors (8-25%), the risk factors traditionally associated with MRSA are a history of hospitalization, surgery, dialysis, residence in a long-term care facility, presence of a permanent indwelling catheter or percutaneous medical device (eg, tracheostomy tube, gastrostomy tube, Foley catheter), or previous isolation of MRSA.

Antibiotics should be administered IV since absorption by other routes is inconsistent given the hypotension and suboptimally performing gastrointestinal tract of seriously ill patients.

Drug Name	Penicillin G (Pfizerpen) -- DOC for use with infections by clostridial species. Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
Adult Dose	10-40 million U IV qd divided q4-6h
Pediatric Dose	100,000-250,000 U/kg IV qd divided q4h
Contraindications	Documented hypersensitivity
Interactions	Probenecid can increase effects of penicillin; coadministration of tetracyclines can decrease effects of penicillin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in impaired renal function

Drug Name	Clindamycin (Cleocin) -- Lincosamide useful as treatment against serious skin and soft tissue infections caused by most staphylococcal strains. Also effective against aerobic and anaerobic streptococci, except enterococci. Inhibits bacterial protein synthesis by inhibiting peptide chain initiation at bacterial ribosome where it preferentially binds to 50S ribosomal subunit, causing bacterial growth inhibition.
Adult Dose	600-1200 mg IV/IM qd divided q6-8h depending on degree of infection
Pediatric Dose	16-20 mg/kg/d IV/IM divided tid/qid Severe infections: May increase dose to 20-40 mg/kg/d IV/IM divided tid/qid
Contraindications	Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin
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 colitis

Drug Name	Ceftriaxone (Rocephin) -- Third-generation cephalosporin that has broad-spectrum activity against gram-negative organisms, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial cell wall synthesis and inhibits bacterial growth by binding to 1 or more penicillin-binding proteins.
Adult Dose	1-2 g IV qd or divided bid, depending on type and severity of infection; not to exceed 4 g/d
Pediatric Dose	Neonates >7 days: 25-50 mg/kg/d IV; not to exceed 125 mg/d Infants and children: 50-75 mg/kg/d IV divided q12h; not to exceed 2 g/d
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase ceftriaxone levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment; caution in breastfeeding women and allergy to penicillin

Drug Name	Metronidazole (Flagyl) -- Active against various anaerobic bacteria and protozoa. Appears to be absorbed into cells; intermediate-metabolized compounds that are formed bind DNA and inhibit protein synthesis, causing cell death.
Adult Dose	Loading dose: Infuse 15 mg/kg IV over 1 h or 1 g for a 70-kg adult Maintenance dose: Following loading dose, infuse 7.5 mg/kg IV over 1 h q6-8h or 500 mg for a 70-kg adult; not to exceed 4 g/d
Pediatric Dose	Administer as in adults; not to exceed 2 g/d
Contraindications	Documented hypersensitivity
Interactions	May increase toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity of metronidazole; disulfiram reaction may occur with orally ingested ethanol
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in hepatic disease; monitor for seizures and development of peripheral neuropathy

Drug Name	Linezolid (Zyvox) -- Prevents formation of functional 70S initiation complex, which is essential for bacterial translation process. Bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Used as alternative in patients allergic to vancomycin and for treatment of vancomycin-resistant enterococci.
Adult Dose	400-600 mg PO/IV q12h for 10-28 d
Pediatric Dose	Preterm neonate <7 days: 10 mg/kg PO/IV q12h Term neonates to 12 years: 10 mg/kg PO/IV q8h >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	May cause hypertension when used concomitantly with adrenergic agents including pseudoephedrine, sympathomimetic agents, or vasopressor or dopaminergic agents (reduce dose of dopamine or epinephrine if concurrent use required); serotonin syndrome may occur if used concomitantly with serotonergic agents including tricyclic antidepressants, meperidine, dextromethorphan, trazodone, venlafaxine, and selective serotonin reuptake; may cause myelosuppression or pseudomembranous colitis inhibitors
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Has mild MAO inhibitor properties and has potential to have same interactions as other MAO inhibitors; caution in uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or untreated hyperthyroidism, and in patients who are at increased risk for bleeding, have preexisting thrombocytopenia, are receiving concomitant medications that may decrease platelet count or function, or who may require >2 wk of therapy (monitor platelet counts); unnecessary use may lead to development of resistance to drug; may cause peripheral or optic neuropathy

Drug Name	Gentamicin (Gentacidin, Garamycin) -- Aminoglycoside antibiotic used for gram-negative bacterial coverage. Commonly used in combination with an agent with activity against gram-positive organisms and one that covers anaerobes. Not antibiotic of first choice. Consider using when penicillins or other less toxic drugs are contraindicated, when bacterial susceptibility tests and clinical judgment indicate its use, and in mixed infections caused by susceptible strains of staphylococci and gram-negative organisms. Dosing regimens are numerous and are adjusted based on CrCl and changes in volume of distribution. Gentamicin may be administered IV/IM.
Adult Dose	Serious infections and normal renal function: 3 mg/kg/d IV/IM q8h Life-threatening infections: 5 mg/kg/d IV/IM q6-8h Each regimen must be followed by at least a trough level drawn on third or fourth dose, 0.5 h before dosing; may draw a peak level 0.5 h after 30-min infusion Dose may need adjustment in patients diagnosed with renal impairment
Pediatric Dose	<5 years with normal renal function: 2.5 mg/kg/dose IV/IM q8h >5 years: 1.5-2.5 mg/kg/dose IV/IM q8h or 6-7.5 mg/kg/d IV/IM divided q8h; not to exceed 300 mg/d with adjustments for renal function prn (monitor levels as in adults)
Contraindications	Documented hypersensitivity
Interactions	Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; because aminoglycosides enhance effects of neuromuscular blocking agents, prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Drug Name	Vancomycin (Vancocin) -- Potent antibiotic directed against gram-positive organisms and active against enterococci species. Useful to treat septicemia and skin structure infections. Indicated for patients who cannot receive or have failed to respond to penicillins and cephalosporins or for those who have infections with resistant staphylococci. For abdominal penetrating injuries, combine with an agent active against enteric flora and/or anaerobes. To avoid toxicity, assay of vancomycin trough levels after the third dose drawn 0.5 h prior to next dosing currently is recommended. May need to adjust dose in patients diagnosed with renal impairment (use CrCl).
Adult Dose	500-2000 mg/d IV divided tid/qid for 7-10 d
Pediatric Dose	40 mg/kg/d IV divided tid/qid for 7-10 d
Contraindications	Documented hypersensitivity
Interactions	Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal failure and neutropenia

Drug Category: Medicinal gas -- Oxygen is used in an attempt to minimize tissue necrosis caused by clostridial species.

Drug Name	Hyperbaric oxygen (HBO) -- Use is controversial but can be used to supplement surgical debridement and antibiotics. This modality may be particularly helpful in areas where complete surgical resection of necrotic tissue is difficult such as the paraspinal muscles or abdominal wall. Potential benefits include improved neutrophil-mediated killing of bacteria, direct bactericidal effect on anaerobes, improved activity of some antibiotics, and enhanced wound healing. Given its aerotolerance, gas gangrene caused by C septicum may be less amenable to HBO therapy.
Adult Dose	Typical therapy is 100% oxygen at 3 atm of pressure for 90 min with 2-3 dives in first 24 h, followed by 2-3 dives/d for a total of 7-10 dives
Pediatric Dose	Administer as in adults
Contraindications	None reported
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Barotrauma can cause rupture of the middle ear, cranial sinuses, teeth, or lungs Prophylactic myringotomy should be considered; oxygen toxicity can cause reversible myopia, a lower seizure threshold, and pulmonary toxicity

Drug Category: Toxoids -- Used to induce active immunity.

Drug Name	Tetanus toxoid -- Used to induce active immunity against tetanus in selected patients. Immunizing agents of choice for most adults and children >7y are tetanus and diphtheria toxoids. Necessary to administer booster doses to maintain tetanus immunity throughout life. Pregnant patients should receive only tetanus toxoid, not a diphtheria antigen-containing product. In children and adults, may administer into deltoid or midlateral thigh muscles. In infants, preferred site of administration is mid thigh laterally.
Adult Dose	Primary immunization: 0.5 mL IM; administer 2 injections 4-8 wk apart; third dose 6-12 mo after second injection Booster dose: 0.5 mL IM q10y
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; history of any type of neurologic symptoms or signs following administration of this product; FDA recommends that elective tetanus immunization be deferred during any outbreak of poliomyelitis because tetanus toxoid injections are an important cause of provocative poliomyelitis
Interactions	Patients receiving immunosuppressants, including corticosteroids or radiation therapy, may remain susceptible despite immunization due to poor immune response; cimetidine may enhance or augment delayed-hypersensitivity responses to skin-test antigens; avoid concurrent use of medication with systemic chloramphenicol, since it may impair amnestic response to tetanus toxoid; concurrent use of tetanus immune globulin may delay development of active immunity by several days (interaction is nevertheless clinically insignificant and does not preclude concurrent use)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not use to treat actual tetanus infections or for immediate prophylaxis of unimmunized individuals (use instead tetanus antitoxin, preferably human tetanus immune globulin); diminished antibody response to active immunization may be observed in patients receiving immunosuppressive therapy; better to defer primary diphtheria immunization until immunosuppressive therapy discontinued; routine immunization of symptomatic and asymptomatic HIV-infected persons is recommended

Drug Category: Immunoglobulins -- Used to induce passive immunity.

Drug Name	Tetanus immune globulin (Hyper-Tet) -- Used for passive immunization of any person with a wound that may be contaminated with tetanus spores.
Adult Dose	Prophylaxis: 250-500 U IM in opposite extremity to tetanus toxoid lesion Clinical tetanus: 3,000-10,000 U IM
Pediatric Dose	Prophylaxis: 250 U IM in opposite extremity to tetanus toxoid Clinical tetanus: 3,000-10,000 U IM
Contraindications	Documented hypersensitivity; since antibodies in globulin preparation may interfere with immune response to vaccination, do not administer within 3 mo of live virus immune globulin administration; may be necessary to revaccinate persons who received immune globulin shortly after live virus vaccination
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Persons with isolated IgA deficiency have potential for developing antibodies to IgA and could have anaphylactic reactions to subsequent administration of blood products that contain IgA; do not perform skin testing since intradermal injection of concentrated gamma globulin may cause localized area of inflammation and can be misinterpreted, causing medication to be withheld from a patient not allergic to this material; true allergic responses to human gamma globulin administered in prescribed IM manner are extremely rare; do not admix with other medications since usually incompatible

Drug Category: Analgesics -- Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary toilet, and have sedating properties, which are beneficial for patients who have sustained trauma or have sustained injuries.

Drug Name	Morphine sulfate (Astramorph, MS Contin, MSIR, Oramorph) -- DOC for analgesia due to reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Various IV doses are used; commonly titrated until desired effect obtained.
Adult Dose	Starting dose: 0.1 mg/kg IV/IM/SC Maintenance dose: 5-20 mg/70 kg IV/IM/SC q4h Relatively hypovolemic patients: Start with 2 mg IV/IM/SC; reassess hemodynamic effects of dose
Pediatric Dose	Infants and children: 0.1-0.2 mg/kg dose IM/SC q4h prn; not to exceed 15 mg/dose; may initiate at 0.05 mg/kg/dose <6 months: 0.03-0.05 mg/kg IV >6 months: 0.05-0.1 mg/kg IV
Contraindications	Documented hypersensitivity; hypotension; potentially compromised airway where establishing rapid airway control would be difficult
Interactions	Phenothiazines may antagonize analgesic effects of opiate agonists; tricyclic antidepressants, MAO inhibitors, and other CNS depressants may potentiate adverse effects of morphine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hypotension, respiratory depression, nausea, emesis, constipation, urinary retention, atrial flutter, and other supraventricular tachycardias; has vagolytic action and may increase ventricular response rate

Drug Name	Fentanyl citrate (Duragesic, Sublimaze) -- A synthetic opioid that is 75-200 times more potent and has a much shorter half-life than morphine sulfate. Has less hypotensive effects and is safer in patients with hyperactive airway disease than morphine because of minimal-to-no associated histamine release. By itself, it causes little cardiovascular compromise, although addition of benzodiazepines or other sedatives may result in decreased cardiac output and blood pressure. Highly lipophilic and protein-bound. Prolonged exposure leads to accumulation in fat and delays weaning process. Consider continuous infusion because of the short half-life of fentanyl. Parenteral form is DOC for conscious sedation analgesia. Ideal for analgesic action of short duration during anesthesia, and immediate postoperative period. Excellent choice for pain management and sedation with short duration (30-60 min) and easy to titrate. Easily and quickly reversed by naloxone. After initial parenteral dose, subsequent parenteral doses should not be titrated more frequently than q3h or q6h thereafter. Transdermal form is used only for chronic pain conditions in opioid tolerant patients. When using transdermal dosage form, most patients are controlled with 72-h dosing intervals; however, some patients require dosing intervals of 48 h. Easily and quickly reversed by naloxone.
Adult Dose	Emergency: 0.5-2 mcg/kg/dose IM/IV Analgesia: 0.5-1 mcg/kg/dose IM/IV q30-60min Transdermal: Apply a 25 mcg/h system q48-72h
Pediatric Dose	<2 years: 2-3 mcg/kg/dose IM/IV q60min 2-12 years: 1-2 mcg/kg/dose IM/IV q60min >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; hypotension or potentially compromised airway where it would be difficult to establish rapid airway control
Interactions	Phenothiazines may antagonize analgesic effects of opiate agonists; tricyclic antidepressants may potentiate adverse effects of fentanyl when both drugs are used concurrently
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hypotension, respiratory depression, constipation, nausea, emesis, and urinary retention; idiosyncratic reaction, known as chest wall rigidity syndrome, may require neuromuscular blockade in order to increase ventilation