AUTHOR INFORMATION

Section 1 of 12

Authored by Daniel J Dire, MD, FACEP, FAAP, FAAEM, Clinical Associate Professor, Department of Emergency Medicine, University of Texas-Houston

Daniel J Dire, MD, FACEP, FAAP, FAAEM, is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American Academy of Pediatrics, American College of Emergency Physicians, and Association of Military Surgeons of the US

Edited by Theodore Gaeta, DO, MPH, Residency Director, Clinical Associate Professor of Emergency Medicine in Medicine, Department of Emergency Medicine, New York Methodist Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Eddy Lang, MDCM, CCFP (EM), CSPQ, Assistant Professor, Department of Family Medicine, McGill University; Consulting Staff, Department of Emergency Medicine, The Sir Mortimer B Davis-Jewish General Hospital; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Charles V Pollack, Jr, MD, MA, FACEP, Professor, Department of Emergency Medicine, University of Pennsylvania College of Medicine; Chairman, Department of Emergency Medicine, Pennsylvania Hospital

Author's Email:	Daniel J Dire, MD, FACEP, FAAP, FAAEM
Editor's Email:	Theodore Gaeta, DO, MPH

eMedicine Journal, December 1 2005, VOLUME 6, Number 12

INTRODUCTION

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Background: Tetanus is an illness characterized by an acute onset of hypertonia, painful muscular contractions (usually of the muscles of the jaw and neck), and generalized muscle spasms without other apparent medical causes.

Despite widespread immunization of infants and children in the United States since the 1940s, tetanus still occurs in the United States. Currently, tetanus is a severe disease primarily of older adults who are unvaccinated or inadequately vaccinated.

Pathophysiology: Clostridium tetani, an obligate anaerobic gram-positive bacillus, causes tetanus. This bacterium is nonencapsulated and forms spores, which are resistant to heat, desiccation, and disinfectants. The spores are ubiquitous and are found in soil, house dust, animal intestines, and human feces.

Spores that gain entry can persist in normal tissue for months to years. Under anaerobic conditions, these spores geminate and elaborate tetanospasmin and tetanolysin. Tetanolysin is not believed to be of any significance in the clinical course of tetanus. Tetanospasmin that is released by the maturing bacilli is distributed via the lymphatic and vascular circulations to the end plates of all nerves. Tetanospasmin then enters the nervous system peripherally at the myoneural junction and is transported centripetally into neurons of the central nervous system (CNS).

These neurons become incapable of neurotransmitter release. The neurons, which release gamma-aminobutyric acid (GABA) and glycine, the major inhibitory neurotransmitters, are particularly sensitive to tetanospasmin, leading to failure of inhibition of motor reflex responses to sensory stimulation. This results in generalized contractions of the agonist and antagonist musculature characteristic of a tetanic spasm. The shortest peripheral nerves are the first to deliver the toxin to the CNS, which leads to the early symptoms of facial distortion and back and neck stiffness.

Once the toxin becomes fixed to neurons, it cannot be neutralized with antitoxin. Recovery of nerve function from tetanus toxins requires sprouting of new nerve terminals and formation of new synapses.

Frequency:

• In the US: Reported incidence of tetanus has declined substantially since the mid 1940s because of the widespread use of tetanus immunizations (see Image 1). Image 2 shows the reported number of tetanus cases and average annual incidence rates, by state, in the United States from 1998-2000. An average of 43 cases was reported annually. Some suggest that only 40% of tetanus cases are reported to the Centers for Disease Control and Prevention (CDC). Image 3 shows the number of tetanus cases reported, average annual incidence rates, and survival status of patients, by age group, from 1998-2000. The lowest average annual number of cases for a 3-year period in the United States was 41 cases per year during 1995-1997.
  
  

  Of the 130 cases of tetanus reported in the United States from 1998-2000, California and Texas had the highest reported number of cases. All 50 states require that children be vaccinated prior to admission to public schools. More than 96% of children have received 3 or more diphtheria and tetanus toxoids plus pertussis (DTP) vaccinations by the time they begin school. The annual incidence of tetanus has dropped to fewer than 50 cases per year in the United States. The incidence of tetanus in people who use injection drugs increased 7.4%, from 3.6% of all cases in 1991-1994 to 11% of cases in 1995-1997. People who use injection drugs accounted for 15% of the tetanus cases in the United States from 1998-2000 (see Image 4). Of the 19 people who used injection drugs and contracted tetanus from 1998-2000, only 1 reported an acute injury.
  
  

  Most tetanus cases occur among people who are inadequately vaccinated and who sustain an acute injury.

• Internationally: Worldwide, tetanus is predominantly a disease of underdeveloped countries located in warm, damp climates. Tetanus affects all age groups, with the highest prevalence found in newborns and young people. In 1992, an estimated 578,000 infant deaths occurred due to neonatal tetanus. In the beginning of the 1990s, an estimated 360,000 cases and 140,000 deaths occurred each year from nonneonatal tetanus. Tetanus is one of the target diseases of the World Health Organization Expanded Program on Immunization. Overall, the annual incidence of tetanus is 0.5-1 million cases.
  
  

  Developed nations have incidences of tetanus similar to those observed in the United States. For instance, only 126 cases of tetanus were reported in England and Wales in 1984-1992.

Mortality/Morbidity: Overall, the mortality rate is approximately 45%. Clinical tetanus is less severe among patients who have a history of receiving a primary series of tetanus toxoid sometime during their life as compared with patients who are inadequately vaccinated or unvaccinated. The mortality rate in the United States is 6% for individuals who had previously received 1-2 doses of tetanus toxoid compared with 15% for individuals who were unvaccinated.

• The case-fatality ratio in the United States was 18% from 1998-2000 and 11% from 1995-1997; a case-fatality ratio of 91% was reported in 1947.

• The mortality rate is highest for people older than 60 years (40%) compared with those aged 20-59 years (8%). From 1998-2000, 75% of the deaths in the United States were in patients older than 60 years.

• The mortality rate is 30% for people who require mechanical ventilation but only 4% for those who do not.

Race: From 1998, the incidence of tetanus in the United States was highest among Hispanics (0.38 cases per million population), followed by whites (0.13 cases per million population), and then African Americans (0.12 cases per million population).

Sex: A difference in the levels of tetanus immunity exists between the sexes.

• Overall, men are believed to be better protected than women, perhaps because of additional vaccinations administered during military service or professional activities.

• In the United States from 1998-2000, the incidence of tetanus in males aged 59 years and younger was 2.8 times higher than in females in the same age range.

• In developing countries, women have an increased immunity where tetanus toxoid is administered to women of childbearing age to prevent neonatal tetanus.

Age: The incidence of tetanus increases with advancing age. Of the patients with tetanus in the United States, 36% are older than 59 years and only 9% are younger than 20 years.

CLINICAL

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History:

• From 1995-2000, 81% of cases in the United States were generalized tetanus, 15% were localized, 3% were cephalic, and 1 case of neonatal tetanus was reported. From 1995-1997, 54% of the reported cases in the United States had an unknown tetanus vaccination history, 22% had no known previous tetanus vaccination, 9% had 1 previous dose, 3% had 2 previous doses, 3% had 3 previous doses, and 9% had 4 or more previous doses.

• The last reported case of neonatal tetanus in the United States was in 1998; this was only the second case since 1989.

• Most reported cases of tetanus worldwide are the neonatal type.

• The median incubation period is 7 days, and, for most cases (73%), incubation ranges from 4-14 days.

• The incubation period is shorter than 4 days in 15% of cases and longer than 14 days in 12% of cases.

• Patients with clinical manifestations occurring within 1 week of an injury have more severe clinical courses.

• Patients with generalized tetanus present with trismus (ie, lockjaw) in 75% of cases.

• Other presenting complaints include stiffness, neck rigidity, dysphagia, restlessness, and reflex spasms.

• Subsequently, muscle rigidity becomes the major manifestation.

• Muscle rigidity spreads from the jaw and facial muscles over the next 24-48 hours to the extensor muscles of the limbs.

• Dysphagia occurs in moderately severe tetanus due to pharyngeal muscle spasms, and onset is usually insidious over several days.

• Reflex spasms develop in most patients and can be triggered by minimal external stimuli such as noise, light, or touch. The spasms last seconds to minutes; become more intense; increase in frequency with disease progression; and can cause apnea, fractures, dislocations, and rhabdomyolysis.

• Laryngeal spasms can occur at any time and can result in asphyxia.

• Sustained contraction of facial musculature produces a sneering grin expression known as risus sardonicus.

Physical:

• The lower extremity is the site of antecedent acute injury in 52% of patients, the upper extremity is the site of antecedent injury in 34% of patients, and head or trunk is the site of antecedent injury in 5% of patients.

• Autonomic dysfunction in patients with severe tetanus manifests as extremes in blood pressure, dysrhythmias, and cardiac arrest.

• Neonatal tetanus presents with an inability to suck 3-10 days after birth. Presenting symptoms include irritability, excessive crying, grimaces, intense rigidity, and opisthotonus.

• Tetanic seizures may occur and portend a poor prognosis.

• Frequency and severity of seizures are related to severity of the disease.

• Seizures resemble epileptic seizures with the presence of a sudden burst of tonic contractions.

• However, the patient does not lose consciousness and usually experiences severe pain.

• Seizures frequently occur in the muscle groups causing opisthotonos, flexion and abduction of the arms, clenching of the fists against the thorax, and extension of the lower extremities.

• Localized tetanus is characterized by painful spasms of the group of muscles in close proximity to the site of injury. This disorder may persist for several weeks but is usually self-limiting.

• Cephalic tetanus is usually secondary to chronic otitis media or head trauma.

• Cephalic tetanus is characterized by variable cranial nerve (CN) palsies; CN VII is most frequently involved.

• Ophthalmoplegic tetanus is a variant that develops after penetrating eye injuries and results in CN III palsies and ptosis.

• Patients with cephalic tetanus who are untreated progress to generalized tetanus.

• Patients with tetanus may present with abdominal tenderness and guarding, mimicking an acute abdomen. Exploratory laparotomies have been performed before the correct diagnosis was apparent.

• Tetanospasmin has a disinhibitory effect on the autonomic nervous system (ANS).

• ANS dysfunction becomes progressively evident as the level of toxin in the CNS increases.

• ANS disturbances, such as sweating, fluctuating blood pressure, episodic tachydysrhythmia, and increased release of catecholamines, are observed.

• Drugs with beta-blocker effects have been used to control the cardiovascular manifestations of ANS instability, but they also have been associated with increased risk of sudden death.

Causes:

• Only 12-14% of patients with tetanus in the United States have received a primary series of tetanus toxoid. During 1998-2000, only 6% of all patients with tetanus were known to be current with tetanus immunization, with no fatal cases reported among this group.

• In 73% of patients with tetanus in the United States, tetanus occurred after an acute injury, including puncture wounds (50%), lacerations (33%), and abrasions (9%).

• Of those who obtained medical treatment of their injury in the United States from 1998-2000, 96% were administered tetanus immune globulin as part of their treatment; 55% of patients required the use of assisted ventilation and 31% of these patients died.

• Stepping on a nail accounted for 32% of the puncture wounds.

• Tetanus can occur in burn victims; in patients receiving intramuscular injections; in persons obtaining a tattoo; and in persons with frostbite, dental infections (eg, periodontal abscesses), penetrating eye injuries, and umbilical stump infections.

• Other reported risk factors include diabetes, chronic wounds (eg, skin ulcers, abscesses, gangrene), parenteral drug abuse, and recent surgery (4% of US cases).

• Twelve percent of patients with tetanus in the United States from 1998-2000 had diabetes (with a mortality rate of 31%) compared with 2% during 1995-1997. Of these patients, 69% had acute injuries while 25% had gangrene or a diabetic ulcer.

• The median time interval between surgery and onset of tetanus is 7 days.

• Tetanus has been reported after tooth extractions, root canal therapy, and intraoral soft tissue trauma.

• Worldwide risk factors for neonatal tetanus are as follows:

• Unvaccinated mothers, home delivery, and unhygienic cutting of the umbilical cord increase susceptibility to tetanus.

• History of neonatal tetanus in a previous child is a risk factor for subsequent neonatal tetanus.

• Potentially infectious substances applied to the umbilical stump (eg, animal dung, clarified butter) are risk factors for neonates.

• Immunity from tetanus decreases with advancing age.

• Serologic testing for immunity has revealed a low level among elderly individuals in the United States.

• Approximately 50% of adults older than 50 years are nonimmune because they never were vaccinated or do not receive appropriate booster doses.

• Prevalence of immunity to tetanus in the United States is greater than 80% for those aged 6-39 years but only 28% for persons older than 70 years.

DIFFERENTIALS

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Conversion Disorder
Dislocations, Mandible
Encephalitis
Hypocalcemia
Meningitis
Peritonsillar Abscess
Rabies
Spider Envenomations, Widow
Stroke, Hemorrhagic
Subarachnoid Hemorrhage
Toxicity, Medication-Induced Dystonic Reactions

Other Problems to be Considered:

Intraoral disease
Odontogenic infections
Globus hystericus
Hepatic encephalopathy
Hysteria
Strychnine poisoning
Acute abdomen
Intracranial hemorrhage

WORKUP

Section 5 of 12

Lab Studies:

• No specific laboratory tests exist for determining the diagnosis of tetanus. The diagnosis is clinically based on the presence of trismus, dysphagia, generalized muscular rigidity, and/or spasm.

• Laboratory studies may demonstrate a moderate peripheral leukocytosis.

Other Tests:

• An assay for antitoxin levels is not readily available. However, a level of 0.01 IU/mL or greater in serum is generally considered protective, making the diagnosis of tetanus less likely.

• Cerebral spinal fluid (CSF) study findings are usually within normal limits.

Procedures:

• The spatula test is one diagnostic bedside test.

• This simple test involves touching the oropharynx with a spatula or tongue blade.

• This test typically elicits a gag reflex, and the patient tries to expel the spatula (ie, a negative test result).

• If tetanus is present, patients develop a reflex spasm of the masseters and bite the spatula (ie, a positive test result).

• In 400 patients, this test had a sensitivity of 94% and a specificity of 100%.

• No adverse sequelae from this procedure (eg, laryngeal spasm) were reported.

TREATMENT

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Emergency Department Care: Treatment of tetanus is directed toward the treatment of muscle spasm, prevention of respiratory and metabolic complications, neutralization of circulating toxin to prevent the continued spread, and elimination of the source.

• Admit patients to the ICU. Due to risk of reflex spasms, maintain a dark and quiet environment for the patient. Avoid unnecessary procedures and manipulations.

• Seriously consider prophylactic intubation in all patients with moderate-to-severe clinical manifestations. Intubation and ventilation are required in 67% of patients.

• Attempting endotracheal intubation may induce severe reflex laryngospasm; prepare for emergency surgical airway control. Rapid sequence intubation techniques (eg, with succinylcholine) are recommended to avoid this complication.

• Perform tracheostomy in patients requiring intubation for more than 10 days. Tracheostomy has also been recommended after onset of the first generalized seizure.

• Surgical therapy includes debridement of wounds to remove organisms and to create an aerobic environment.

• The current recommendation is to excise at least 2 cm of normal viable-appearing tissue around the wound margins.

• Incise and drain abscesses.

• Delay any wound manipulation until several hours after administration of antitoxin due to risk of releasing tetanospasmin into the bloodstream.

• Institute prevention measures for deep venous thrombosis, gastrointestinal ulcer, and decubitus ulcer.

• The maintenance of nutrition is extremely important and should be carried out in seriously ill patients via nasoduodenal tubes, gastrostomy tube feedings, or parenteral hyperalimentation.

Consultations:

• An intensive care medicine specialist should be the primary physician coordinating the patient's care.

• Consult a pulmonary medicine specialist after admission to the ICU for patients with severe respiratory symptoms or those requiring mechanical ventilation.

• Consult an anesthesiologist after admission to the ICU if intrathecal baclofen is to be administered.

MEDICATION

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Drugs used to treat muscle spasm, rigidity, and tetanic seizures include sedative-hypnotic agents, general anesthetics, centrally acting muscle relaxants, and neuromuscular blocking agents. Antibiotics are used to prevent multiplication of C tetani, thus halting production and release of toxins.

Drug Category: Anticonvulsants -- Sedative-hypnotic agents are the mainstays of tetanus treatment. Benzodiazepines are the most effective primary agents for muscle spasm prevention and work by enhancing GABA inhibition. Diazepam is the most frequently studied and used drug. Diazepam reduces anxiety, produces sedation, and relaxes muscles.
Phenobarbital is another anticonvulsant that may be used to prolong effects of diazepam. Phenobarbital also is used to treat severe muscle spasms and provide sedation when neuromuscular blocking agents are used.

Drug Name	Diazepam (Valium) -- Mainstay of treatment of tetanic spasms and tetanic seizures. Depresses all levels of CNS, including limbic and reticular formation, possibly by increasing activity of GABA, a major inhibitory neurotransmitter.
Adult Dose	Mild spasms: 5-10 mg PO q4-6h prn Moderate spasms: 5-10 mg IV prn Severe spasms: Mix 50-100 mg in 500 mL D5W and infuse at 40 mg/h
Pediatric Dose	Mild spasms: 0.1-0.8 mg/kg/d PO divided tid/qid Moderate or severe spasms: 0.1-0.3 mg/kg IV q4-8h
Contraindications	Documented hypersensitivity; narrow-angle glaucoma
Interactions	Toxicity of benzodiazepines in CNS is increased when used concurrently with alcohols, phenothiazines, barbiturates, and MAOIs; cisapride can increase diazepam levels significantly
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients receiving other CNS depressants; caution in patients with low albumin levels or hepatic failure because diazepam toxicity may increase

Drug Name	Phenobarbital (Barbita, Luminal) -- Drug dose must be small enough so that respirations are not depressed. If patient is already on a ventilator, higher doses may provide desired sedation.
Adult Dose	1 mg/kg IM q4-6h; not to exceed 400 mg/d
Pediatric Dose	5 mg/kg/d IV/IM divided tid/qid
Contraindications	Documented hypersensitivity; marked impairment of liver function; severe respiratory disease; nephritic patients
Interactions	May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities also may occur)
Pregnancy	D - Unsafe in pregnancy
Precautions	In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia since adverse reactions can occur; caution in myasthenia gravis and myxedema

Drug Category: Skeletal muscle relaxants -- These agents can inhibit both monosynaptic and polysynaptic reflexes at spinal level, possibly by hyperpolarization of afferent terminals.

Drug Name	Baclofen (Lioresal) -- Intrathecal (IT) baclofen, a centrally acting muscle relaxant, has been used experimentally to wean patients off the ventilator and to stop diazepam infusion. IT baclofen is 600 times more potent than PO baclofen. Repeated IT injections have been efficacious in limiting duration of artificial ventilation or preventing intubation. May induce hyperpolarization of afferent terminals and inhibit both monosynaptic and polysynaptic reflexes at spinal level. Entire dose of baclofen is administered as a bolus injection. Dose may be repeated after 12 h or more if spontaneous paroxysms return. Continuous IT baclofen has been reported in a very small number of patients with tetanus. Refer to manufacturer's product information on Lioresal IT for further information.
Adult Dose	<55 years: 1000 mcg IT >55 years: 800 mcg IT
Pediatric Dose	<16 years: 500 mcg IT >16 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Opiate analgesics, benzodiazepines, alcohol, TCAs, guanabenz, MAOIs, clindamycin, and hypertensive agents may increase baclofen effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with history of autonomic dysreflexia and when spasticity is used to obtain increased function; autonomic dysreflexia can result from withdrawal of this medication

Drug Name	Dantrolene (Dantrium) -- Stimulates muscle relaxation by modulating skeletal muscle contractions at a site beyond the myoneural junction and by acting directly on the muscle. Not FDA approved for use in tetanus but has been described in a small number of case reports.
Adult Dose	1 mg/kg IV over 3 h; repeat q4-6h prn
Pediatric Dose	0.5 mg/kg IV bid initial; increase to 0.5 mg/kg IV bid/qid, then by increments of 0.5-3 mg/kg bid/qid prn; not to exceed 100 mg qid
Contraindications	Documented hypersensitivity; active hepatic disease (hepatitis, cirrhosis)
Interactions	Toxicity may increase with coadministration of clofibrate and warfarin; coadministration with estrogen may increase hepatotoxicity in women >35 y
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause hepatotoxicity (use only for recommended indications); caution in impaired pulmonary function and severe cardiac insufficiency; may cause photosensitivity with exposure to sunlight

Drug Category: Antitoxins -- These agents are used to neutralize any toxin that has not reached the CNS.

Drug Name	Tetanus immune globulins (Hyper-Tet, Bay-Tet) -- Used as prophylaxis against tetanus and to treat patients with circulating tetanus toxin. TIG provides passive immunity. TIG should be used to treat all patients with active tetanus, in combination with other supportive and therapeutic treatments. Should also be used to prevent tetanus in patients with inadequate or unknown immunization status after an acute injury.
Adult Dose	Prophylaxis: 250-500 U IM in opposite extremity to tetanus toxoid Clinical tetanus: 3,000-10,000 U IM
Pediatric Dose	Prophylaxis: 250 U IM in opposite extremity to tetanus toxoid Clinical tetanus: Administer as in adults
Contraindications	Patients with hypersensitivity to horse or cow proteins should not receive the equine or bovine antitoxins; do not inject in same site or with same syringe as tetanus toxoid; not to be administered intravenously
Interactions	Live-virus vaccines may not replicate successfully, and antibody response could be reduced when vaccine is administered after tetanus immune globulin because of presence of antibodies in the immune globulin; live-virus vaccines should ideally be administered at least 3 mo after therapy with tetanus immune globulin; if administration of an immune globulin preparation becomes necessary because of exposure to disease, live-virus vaccines can be given simultaneously with immune globulin at site remote from that chosen for immune globulin; vaccine virus replication and stimulation of immunity occurs 1-2 wk after vaccination, therefore, if interval between administration of vaccine and immune globulin is <14 d or if they were administered simultaneously, vaccination should be repeated at least 3 mo after immune globulin preparation was given, unless serologic testing indicates that adequate antibodies were formed
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with prior systemic allergic reactions following administration human immunoglobulin preparations; caution in severe thrombocytopenia or any coagulation disorder that would contraindicate IM injections

Drug Category: Antibiotics -- Administer to patients with clinical tetanus. However, efficacy is questioned. Theoretically, antibiotics may prevent multiplication of C tetani, thus halting production of toxin. Nevertheless, a study of 364 patients found no difference in fatality rates between patients who received antibiotics and those who did not. Penicillin G is the drug of choice. Metronidazole is considered by some to be a better drug. One study demonstrated a lower mortality for patients administered metronidazole compared to penicillin. Tetracycline is an alternative drug for patients who are allergic to penicillin or metronidazole. Large doses of antibiotics are recommended to favor diffusion into devitalized tissue.

Drug Name	Penicillin G (Pfizerpen) -- Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. A 10- to 14-d course of treatment is recommended. Large IV doses of penicillin may cause hemolytic anemia and neurotoxicity. Cardiac arrest has been reported in patients administered massive doses of penicillin G potassium. Patients with renal failure are particularly at risk.
Adult Dose	10-24 million U/d IV/IM divided qid
Pediatric Dose	100,000-250,000 U/kg/d IV/IM divided qid
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	Metronidazole (Flagyl) -- Active against various anaerobic bacteria and protozoa. Appears to be absorbed into cells, and intermediate-metabolized compounds that are formed bind DNA and inhibit protein synthesis, causing cell death. A 10- to 14-d course of treatment is recommended. Some consider this the DOC since penicillin G is also a GABA agonist, which may enhance effects of the toxin.
Adult Dose	500 mg PO q6h or 1 g IV q12h; not to exceed 4 g/d
Pediatric Dose	15-30 mg/kg/d IV divided q8-12h; not to exceed 2 g/d
Contraindications	Documented hypersensitivity; first trimester of pregnancy
Interactions	Cimetidine may increase toxicity of metronidazole; may increase effects of anticoagulants; may increase toxicity of lithium and phenytoin; disulfiramlike 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	Doxycycline (Vibramycin, Doxychel) -- Inhibits protein synthesis and thus bacterial growth by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria. A 10- to 14-d course of treatment is recommended.
Adult Dose	100 mg PO/IV q12h
Pediatric Dose	<8 years: Not recommended <100 lb (45 kg): 2 mg/lb/d (4.4 mg/kg/d) PO/IV divided bid >100 lb (45 kg): Administer as in adults
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Category: Neuromuscular blocking agents -- These agents inhibit the transmission of nerve impulses at neuromuscular junctions of skeletal muscles and/or autonomic ganglia.

Drug Name	Vecuronium (Norcuron) -- Prototypic, nondepolarizing neuromuscular blocking agent that reliably results in muscular paralysis. For maintenance of paralysis, a continuous infusion may be used. Infants are more sensitive to neuromuscular blockade activity, and although the same dose is used, recovery is prolonged by 50%. Not recommended for use in neonates.
Adult Dose	0.08-0.1 mg/kg IV; may reduce to 0.05 mg/kg if patient has been treated with succinylcholine Maintenance of paralysis: 0.025-0.1 mg/kg/h IV; may titrate to desired train-of-4 response (commonly 2 of 4 twitches)
Pediatric Dose	7 weeks to 1 year: 0.08-0.1 mg/kg/dose followed by maintenance dose of 0.05-0.1 mg/kg q1h prn 1-10 years: May require higher initial dose and more frequent supplementation >10 years: Administer as in adults
Contraindications	Documented hypersensitivity; myasthenia gravis or related syndromes
Interactions	When vecuronium is used concurrently with inhalational anesthetics, neuromuscular blockade is enhanced; renal or hepatic failure as well as concomitant administration of steroids may result in prolonged blockade despite withdrawal of the agent
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	In myasthenia gravis or myasthenic syndrome, small doses of vecuronium may have profound effects

FOLLOW-UP

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Complications:

• Prior to 1954, asphyxia from tetanic spasms was the usual cause of death. However, with the advent of neuromuscular blockers, mechanical ventilation, and pharmacologic control of spasms, sudden cardiac death has become the leading cause of death. Sudden cardiac death has been attributed to excessive catecholamine productions, direct action of tetanospasmin, or tetanolysin on the myocardium.

• Further complications include the following:

• Long bone fractures

• Glenohumeral joint and temporomandibular joint dislocations

• Hypoxic injury, aspiration pneumonia, and pulmonary emboli

• Adverse effects of autonomic instability, including hypertension and cardiac dysrhythmias

• Paralytic ileus, pressure sores, and urinary retention

• Malnutrition and stress ulcers

• Coma, nerve palsies, neuropathies, psychological aftereffects, and flexion contractures

Prognosis:

• The prognosis is dependent on incubation period, time from spore inoculation to first symptom, and time from first symptom to first tetanic spasm.

• In general, shorter intervals indicate more severe tetanus and a poorer prognosis.

• Patients usually survive tetanus and return to their predisease state of health.

• Recovery is slow and usually occurs over 2-4 months.

• Some patients remain hypotonic.

• Clinical tetanus does not produce a state of immunity; therefore, patients who survive the disease require active immunization with tetanus toxoid to prevent a recurrence.

Patient Education:

• For excellent patient education resources, visit eMedicine’s Infections Center. Also, see eMedicine’s patient education article Tetanus.

MISCELLANEOUS

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Special Concerns:

• Prevention of tetanus is accomplished through vaccination with DTP at ages 2, 4, 6, and 12-18 months and 4-6 years.

• For an unimmunized person aged 7 years or older, administer tetanus and adult-strength diphtheria toxoids (Td) with a subsequent dose 1-2 months later and a third dose 6-12 months after the second dose.

• Secondary prevention of tetanus is accomplished postexposure through appropriate wound cleansing and debridement and the administration of Td and human tetanus immune globulin (TIG), when indicated. Consider the following wounds to be prone to tetanus: those present longer than 6 hours, deep (>1 cm), grossly contaminated, exposed to saliva or feces, stellate, and ischemic or infected (including abscesses), as well as avulsions, punctures, or crush injuries.

• Administer Td or DTP intramuscularly to patients with tetanus-prone wounds if they are younger than 7 years and if it has been more than 5 years since their last dose of tetanus.

• Administer TIG (250-500 U IM in opposite extremity) if patients previously have received fewer than 3 doses of tetanus toxoid and for patients aged 60 years or older.

• In adults without tetanus-prone wounds, administer Td to patients who previously have received fewer than 3 doses of tetanus toxoid or if more than 10 years have passed since their last dose.

• Review the immunization status for all patients who present to an ED for any care (regardless of chief complaint). Administer immunizations if a lapse of more than 10 years has occurred since their last booster.

• The Advisory Committee on Immunization Practices recommends vaccination at primary care visits for adolescents aged 11-12 years and for adults aged 50 years, review of vaccination histories, and updating of their tetanus vaccination status. This is in addition to recommending booster doses of tetanus-diphtheria toxoid every 10 years.

• Worldwide, neonatal tetanus may be eliminated by increasing immunizations in women of childbearing age, especially pregnant women, and by improving maternity care.

• Tetanus toxoid twice during pregnancy (4-6 wk apart, preferably in the last 2 trimesters) and again at least 4 weeks before delivery is recommended for previously unimmunized gravid women.

• Maternal antitetanus antibodies are passed to the fetus, and this passive immunity is effective for many months.

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which of the following bacteria causes tetanus?

A: An aerobic bacillus
B: A gram-negative bacillus
C: An anaerobic gram-negative bacillus
D: An anaerobic gram-positive bacillus
E: None of the above

The correct answer is D: Tetanus is caused by the obligate gram-positive bacillus, Clostridium tetani. This bacterium is nonencapsulated and forms spores that are resistant to heat, desiccation, and disinfectants.

CME Question 2: Which of the following lab tests confirms the diagnosis of tetanus?

A: Tetanus assay for antitoxin
B: CBC with elevated eosinophils
C: CBC with a moderate peripheral leukocytosis
D: CBC with elevated neutrophils
E: None of the above

The correct answer is E: No specific laboratory tests exist for determining the diagnosis of tetanus. An assay for antitoxin levels is not readily available or confirmatory. Laboratory studies may demonstrate a moderate peripheral leukocytosis. The diagnosis is made clinically based on the presence of trismus, dysphagia, generalized muscular rigidity, and/or spasm.

Pearl Question 1 (T/F): The spatula test may help confirm the diagnosis of tetanus.

The correct answer is True: The spatula test may help confirm the diagnosis of tetanus; this simple test involves touching the oropharynx with a spatula or tongue blade. The test normally elicits a gag reflex, and the patient tries to expel the spatula (ie, a negative test result). If tetanus is present, patients develop a reflex spasm of the masseters and bite the spatula (ie, a positive test result).

Pearl Question 2 (T/F): Tetanus is common in the United States, with thousands of cases reported every year.

The correct answer is False: Tetanus is rare in the United States, with 50-100 patients presenting each year; internationally, the disease is very common. Worldwide, 578,000 infant deaths occurred due to neonatal tetanus in 1992, and more than 140,000 deaths occurred due to nonneonatal tetanus.

Pearl Question 3 (T/F): Adult patients with tetanus usually present with lockjaw.

The correct answer is True: Of adult patients with tetanus, 75% present with lockjaw; other presenting symptoms include stiffness, neck rigidity, dysphagia, restlessness, and reflex spasms.

Pearl Question 4 (T/F): Neonates with tetanus present with inability to suck.

The correct answer is True: Neonates with neonatal tetanus present with inability to suck 3-10 days after birth. Other manifestations include irritability, excessive crying, grimaces, intense rigidity, and opisthotonus.

PICTURES

Section 11 of 12

Caption: Picture 1. Image from Tetanus morbidity and mortality rates, by year. Pascual FB, McGinley EL, Zanardi LR, et al: Tetanus surveillance--United States, 1998--2000. MMWR Surveill Summ 2003 Jun 20; 52(3): 1-8.
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Caption: Picture 2. Image from Number of tetanus cases reported and average annual incidence rates, by state. Pascual FB, McGinley EL, Zanardi LR, et al: Tetanus surveillance--United States, 1998--2000. MMWR Surveill Summ 2003 Jun 20; 52(3): 1-8.
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Caption: Picture 3. Image from Number of tetanus cases reported, average annual incidence rates, and survival status of patients, by age group. Pascual FB, McGinley EL, Zanardi LR, et al: Tetanus surveillance--United States, 1998--2000. MMWR Surveill Summ 2003 Jun 20; 52(3): 1-8.
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Caption: Picture 4. Image from Number of tetanus cases reported among persons with diabetes or injection-drug use (IDU), by age group. Pascual FB, McGinley EL, Zanardi LR, et al: Tetanus surveillance--United States, 1998--2000. MMWR Surveill Summ 2003 Jun 20; 52(3): 1-8.
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BIBLIOGRAPHY

Section 12 of 12

• Ahmadsyah I, Salim A: Treatment of tetanus: an open study to compare the efficacy of procaine penicillin and metronidazole. Br Med J (Clin Res Ed) 1985 Sep 7; 291(6496): 648-50[Medline].
• Apte NM, Karnad DR: Short report: the spatula test: a simple bedside test to diagnose tetanus. Am J Trop Med Hyg 1995 Oct; 53(4): 386-7[Medline].
• Bardenheier B, Prevots DR, Khetsuriani N: Tetanus surveillance--United States, 1995-1997. MMWR CDC Surveill Summ 1998 Jul 3; 47(2): 1-13[Medline].
• Checketts MR, White RJ: Avoidance of intermittent positive pressure ventilation in tetanus with dantrolene therapy. Anaesthesia 1993 Nov; 48(11): 969-71[Medline].
• Galazka A, Gasse F: The present status of tetanus and tetanus vaccination. Curr Top Microbiol Immunol 1995; 195: 31-53[Medline].
• Groleau G: Tetanus. Emerg Med Clin North Am 1992 May; 10(2): 351-60[Medline].
• Izurieta HS, Sutter RW, Strebel PM, et al: Tetanus surveillance--United States, 1991-1994. MMWR CDC Surveill Summ 1997 Feb 21; 46(2): 15-25[Medline].
• Kefer MP: Tetanus. Am J Emerg Med 1992 Sep; 10(5): 445-8[Medline].
• Knight AL, Richardson JP: Management of tetanus in the elderly. J Am Board Fam Pract 1992 Jan-Feb; 5(1): 43-9[Medline].
• Murphy SM, Hegarty DM, Feighery CS, et al: Tetanus immunity in elderly people. Age Ageing 1995 Mar; 24(2): 99-102[Medline].
• Pascual FB, McGinley EL, Zanardi LR, et al: Tetanus surveillance--United States, 1998--2000. MMWR Surveill Summ 2003 Jun 20; 52(3): 1-8[Medline].
• Richardson JP, Knight AL: The management and prevention of tetanus. J Emerg Med 1993 Nov-Dec; 11(6): 737-42[Medline].
• Saissy JM, Demaziere J, Vitris M, et al: Treatment of severe tetanus by intrathecal injections of baclofen without artificial ventilation. Intensive Care Med 1992; 18(4): 241-4[Medline].
• Sanders RK: The management of tetanus 1996. Trop Doct 1996 Jul; 26(3): 107-15[Medline].

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