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  Tetanus is caused by Clostridium tetani and is a toxin-mediated disease.

  
  
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  Although rare in the USA, worldwide there are between 500,000 and 1 million cases a year, with over 200,000 deaths.

  
  
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  It characterized by trismus, dysphagia, and localized muscle rigidity near a site of injury, often progressing to severe generalized muscular spasms complicated by respiratory failure and cardiovascular instability.

  
  
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  The diagnosis of tetanus is made on clinical grounds alone. A clinical diagnosis of presumed tetanus is sufficient to initiate treatment.

  
  
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  Patients with tetanus should be managed in an ICU. In severe cases, the first priority is control of the airway to ensure adequate ventilation and correction of hypotension related to hypovolemia and/or autonomic instability.

  
  
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  Antitoxin therapy with human tetanus immune globulin is given intramuscularly (500-3000 IU) as early as possible.

  
  
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  Treatment to limit continued production and absorption of toxin includes surgical debridement of the site of injury and antimicrobial therapy with intravenous metronidazole.

  
  
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  Traditionally muscle rigidity and spasms have been treated with high-dose benzodiazepines and narcotics. However, intravenous magnesium therapy should also be considered.

  
  
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  Cardiovascular instability due to autonomic dysfunction is managed by ensuring normovolemia and using benzodiazepine, narcotic, and/or magnesium sulfate infusions when needed.

  
  
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  Supportive measures include early provision of nutrition, correction of electrolyte disturbances, subcutaneous heparin administration for prophylaxis of deep venous thrombosis, and prompt antimicrobial therapy for nosocomial infection.

  
  
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  With meticulous management of the manifestations of this disease and careful attention to prevention of its major complications, complete recovery is possible in most cases.

Tetanus is often a disease of otherwise healthy active people. Fully developed tetanus is frequently rapidly fatal unless the patient is supported through a lengthy period of painful muscle spasms complicated by respiratory failure, cardiovascular instability, and increased risk of pulmonary embolism and nosocomial infection. In developed countries, this disease is likely to remain an uncommon but challenging problem that demands an alert and aggressive approach to initial diagnosis and management. If this early management is coupled with attentive supportive care and avoidance of complications over a period of prolonged critical illness, excellent outcomes are possible in most cases.

Historically, tetanus was a feared complication of wound infections. This Clostridium tetani toxin-mediated disease is one of several toxin-mediated diseases resulting from wound infections, along with staphylococcal and streptococcal toxic shock syndrome, wound botulism, and wound diphtheria. Since the advent of routine vaccination after trauma injury and passive immunization for grossly contaminated wounds, tetanus has become uncommon in the United States with an average of 43 cases annually from 1998 to 2000.¹ Worldwide it is still a major cause of morbidity and mortality, and remains one of the WHO targeted diseases. Overall, 500,000 to 1 million cases occur worldwide each year, with 213,000 deaths, the majority in children less than 5 years of age. This is mainly due to inadequate vaccination, either because of access to care or neonatal infections before vaccination is given. The male:female ratio is approximately 3:2, representing a greater incidence of tetanus-prone wounds in males. If patients have access to supportive care for respiratory failure and cardiovascular instability, recovery is possible in most cases, although the road to recovery can be quite long and fraught with complications of critical illness, most notably nosocomial infections and venous thrombosis.

Clostridium tetani spores are found in the soil and the gastrointestinal tract of humans and many nonhuman animals. Spores gain access to tissues through trauma and may remain viable for months to years, but the incubation period is usually 7 to 10 days.² The shorter the incubation period, the more severe the symptoms, and this is most likely related to an inoculation effect.³ The spores are resistant to boiling and antiseptics, but are killed by autoclaving at 121°C for 15 minutes.⁴ Usually spores get into tissues from a puncture wound, laceration, or abrasion, but inoculation can also occur from tattoos, injections, burn wounds, frostbite, dental infections, and penetrating eye injuries.⁵ Neonatal cases can occur from umbilical stump infections.

When the spores germinate the bacteria secrete tetanospasmin and tetanolysin. Tetanolysin is a virulence factor that causes local tissue necrosis. Tetanospasmin is the toxin responsible for the clinical syndrome seen in tetanus. It is a very potent toxin, with an estimated minimum lethal dose being 2.5ng/kg of body weight.⁶ Inside the bacteria, the toxin is inactive, but when a bacterial cell dies, the toxin is released and activated by proteases. If toxin is produced in larger amounts, it also accumulates in the lymphatic system of the invaded muscle, enters the bloodstream via the thoracic duct, and is disseminated throughout the body. Toxin passing from blood to skeletal muscle then accumulates in the nerve endings of the motor fibers and proceeds to the ventral horns or cranial nuclei or is taken up by the lymphatic system and recirculated in the blood. The rate of accumulation of toxin in the ventral horns of the spinal cord depends on the length of the neural pathway and the activity of the muscles involved.⁷ Since jaw muscles and spinal postural muscles have short neural pathways to the ventral horns and are continually active in the awake human, this is the likely explanation for trismus and neck stiffness early in the course of the illness.

The toxin cleaves membrane proteins involved in neuroexocytosis and neurons that are involved become incapable of transmitter release.⁸ Tetanospasmin binds to gangliosides on the membranes of local nerve terminals at the myoneural junction. It then enters peripheral neurons and is transported to neurons of the CNS via retrograde axonal transport. Tetanus appears when the toxin reaches spinal neurons. The neurons that are affected secrete inhibitory neurotransmitters, that is, those that secrete GABA and glycine, are more sensitive to the toxin. Neurons that are involved become incapable of transmitter release and as a result there is no inhibition of motor reflex responses. This leads to contractions of agonist and antagonist muscles known as tetanic spasms. Once toxin is fixed to neurons, it cannot be neutralized, even with administration of antitoxin antibodies. New nerve terminals and new synapses must form for resolution, on the order of 4 to 6 weeks.⁹ For this reason, therapy at the point of clinical tetanus is only supportive.

The effect of tetanus toxin on the neuromuscular junction is presynaptic inhibition of acetylcholine release, which can result in paralysis of muscles. Paralysis is less frequent and usually localized to areas of high toxin concentration because the neuromuscular junction is not as sensitive to tetanus toxin as the inhibitory neurons. Autonomic dysfunction occurs later in the course of the disease because of the longer neuronal path. Sympathetic and parasympathetic overactivity has been attributed to impaired neuronal inhibition of the adrenal glands.¹⁰

Because preformed circulating antibody to tetanospasmin can completely prevent development of the disease, tetanus occurs primarily in nonimmunized or inadequately immunized patients, particularly the poor and elderly.^11,12 Although vaccination results in antitoxoid antibodies that neutralize the toxin, disease is still possible in those who have been properly vaccinated and receive appropriate booster doses of vaccine. Many conditions may impair the immune response to vaccine, including advanced HIV infection. The course in these may be atypical and milder.¹³

The majority of cases of tetanus follow some type of trauma or injury; however, in 15% to 25% of cases a portal of entry cannot be determined (cryptogenic tetanus).¹⁴ Portal of entry can range from minor trauma producing a break in the skin, burn injuries, infected umbilical stumps, postoperative sites, ischemic ulcers, the uterus after septic abortions, injection sites of narcotic addicts, and untreated otitis media.¹⁵ Cases of tetanus have been seen in intravenous drug users associated with skin infections caused by use of inadequately sterilized needles.^14,16 The incubation period can range from 3 days to 3 weeks, but cases have occurred after several months. In general, the shorter the incubation period, the more severe the disease. However, a long incubation does not guarantee a mild course. A prodrome of malaise, irritability, and headache has been described but is usually not seen.¹⁷

There are four basic forms of tetanus that can be distinguished clinically: generalized, local, cephalic, and neonatal. Only generalized, local, and cephalic will be described in this chapter. In the adult intensive care unit setting, generalized tetanus is the most likely to be encountered.

GENERALIZED TETANUS

Generalized tetanus accounts for 80% of tetanus seen in clinical practice and is characterized by diffuse muscle rigidity affecting any voluntary muscle group.⁴ As the disease progresses, more muscle groups become involved. A majority of patients (75%) will present with rigidity of the masseter muscle (trismus), which results in difficulty with opening the mouth and chewing. It is not uncommon for these patients to present to a dentist first. Other common manifestations include neck rigidity, stiffness, dysphagia, and reflex spasm. As the disease evolves the main manifestations are muscle rigidity and reflex spasms. Muscle rigidity in the facial muscles results in risus sardonicus (sardonic smile), while opisthotonos is caused by rigidity of the vertebral muscles and antigravity muscles. Vertebral fractures are not uncommon when these muscle groups are involved.¹⁷ Abdominal muscle involvement may mimic peritonitis, while nuchal rigidity can simulate meningitis. Reflex spasms are present in 70% of patients and can be provoked by external stimuli such as noise or manipulation of the patient. These spasms are tonic and clonic in nature and painful. Sustained spasms can lead to exhaustion and hypoxia in patients. Laryngeal spasm may lead to asphyxia; early and aggressive airway management is indicated early in the disease course because laryngeal spasm may occur at any time in the disease course.¹⁵ In the Edmondson and Flowers series of 100 patients, trismus and dysphagia (described as sore throat) were the presenting symptoms in 75 cases and neck and back stiffness in 14 cases. However, in 88 cases, it was possible to demonstrate trismus on initial physical examination.^14,18

Spasms are initially tonic, followed first by high-frequency and then low-frequency clonic activity. In very severe tetanus, spasms may occur so frequently that status epilepticus may be suspected, and may be forceful enough to cause fractures of long bones and of the spine. Spasm-induced damage to muscles can also result in rhabdomyolysis complicated by acute renal failure.¹⁹ Spasms may be initiated by touch, noise, lights, and swallowing, even in the sleeping patient. Spasms severe enough to require treatment may persist for up to 6 weeks.

In addition to being extremely painful, spasms can produce a variety of significant secondary effects. Apnea occurs when spasms involve the respiratory muscles or larynx. Paralysis of skeletal muscles may occur following periods of sustained spasms due to presynaptic inhibition of acetylcholine release at the neuromuscular junction. Similarly, paralysis of urinary bladder musculature together with spasm of perineal muscles has been implicated in causing acute urinary retention. In pregnancy, spasms can cause abortion or miscarriage, although the fetus is not directly affected, since the toxin does not cross the placenta. Inadequately treated spasms can also produce fever, although secondary infection and direct and indirect actions of toxin on hypothalamic temperature regulation are often implicated.

The autonomic nervous system dysfunction of severe tetanus usually occurs 1 to 2 weeks after the onset of the disease but may occur earlier.²⁰ Manifestations of impaired sympathetic inhibition include tachycardia, labile hypertension alternating with hypotension, peripheral vasoconstriction, fever, and profuse sweating. Overactivity of the parasympathetic nervous system causes increased bronchial and salivary gland secretions, bradycardia, and sinus arrest.²¹ These hemodynamic findings are similar to those seen in pheochromocytomas. Additional complications include pulmonary edema, myocardial dysfunction, acute respiratory distress syndrome, pneumonia, sepsis, pulmonary embolism, gastrointestinal bleeding, and poor nutritional status.¹

LOCALIZED TETANUS

Localized tetanus is a less common presentation of tetanus and is characterized by rigidity of the group of muscles in close proximity to the site of injury without systemic signs. The presence of circulating antitoxin prevents the systemic spread of the toxin, but there is not enough antitoxin to stop local toxin uptake at a wound site. The toxin causes painful muscle contractions that can last for weeks. The disease may be mistaken for pain-induced muscle spasms.¹⁷ Local tetanus may develop into generalized tetanus but is usually milder and less likely to be fatal, with mortality of approximately 1%.⁴

CEPHALIC TETANUS

Cephalic tetanus is a rare form of the disease, occurring with otitis media, following head trauma or chronic infection or the head and neck. Cephalic tetanus after scalp or facial injury tends to occur earlier with an incubation period of 1 day to 2 weeks.²² It only involves the cranial nerves and is defined as trismus plus paralysis of one or more cranial nerves. Although the most common cranial nerve involved is VII, any cranial nerve can be affected. Patients can present with a confusing clinical picture that may involve dysphagia, trismus, and focal cranial neuropathies.¹⁷ Isolated paralysis of the facial nerve may be due to Bell palsy or an early manifestation of cephalic tetanus.²³ In cephalic tetanus, cranial nerve palsies may precede trismus.^14,18 Progression to the generalized form can occur with cephalic tetanus and is associated with a poor prognosis.^4,22,24

The diagnosis of tetanus is based on clinical manifestations rather than laboratory tests. In areas where tetanus is endemic diagnosis is relatively easy, but in developed countries where the disease is less prevalent diagnosis can be delayed. The spatula test is a simple test that can be helpful in diagnosis. In the presence of tetanus, the posterior pharyngeal wall will contract due to a reflex contraction of the masseters when touched by a spatula. In a study by Apte and Kanad used the test on 400 patients with suspected tetanus and was found to have sensitivity of 94% and a specificity of 100% for diagnosing tetanus.²⁵

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