Chapter 59. Tetanus

• Tetanus is a toxin-mediated disease caused by Clostridium tetani and 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.
• The diagnosis of tetanus is made on clinical grounds alone. A clinical diagnosis of presumed tetanus is sufficient to initiate treatment.
• 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.
• Antitoxin therapy with human tetanus immune globulin is given intramuscularly (3000 to 6000 IU) as early as possible. In cases that have not yet progressed to generalized spasms, 250 IU given intrathecally by lumbar puncture may be of benefit.
• Treatment to limit continued production and absorption of toxin includes surgical débridement of the site of injury and antimicrobial therapy with intravenous metronidazole.
• Traditionally muscle rigidity and spasms have been treated with high-dose benzodiazepines and narcotics. However, intravenous magnesium therapy should also be considered.
• Cardiovascular instability due to autonomic dysfunction is managed by ensuring normovolemia and using benzodiazepine, narcotic, and/or magnesium sulfate infusions when needed.
• 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.
• 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 one of the best examples of a disease for which modern intensive care can offer a truly major improvement in long-term useful survival. Often a disease of otherwise healthy active people, the fully developed form 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. However, if all these problems are meticulously managed, complete recovery can be expected. 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, coupled with careful attention to supportive care and avoidance of complications over a period of weeks to months to achieve the eventual excellent outcome possible in most cases.

Although tetanus is primarily a disease of underdeveloped countries, there are approximately 36 to 48 cases per year reported in the United States.1 The male:female ratio is approximately 3:2, representing a greater incidence of tetanus-prone wounds in males. 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.1,2 However, in rare instances tetanus has developed in patients who had received their primary series, as well as proper booster doses of toxoid,3,4 so a history of proper immunization does not exclude the diagnosis of tetanus.

The disease is caused by Clostridium tetani, an anaerobic bacterium that exists in both vegetative and sporulated forms and has been isolated from soil, feces of humans and animals, dust, wounds, intact skin, catgut, and talcum powder. During unfavorable conditions the organism exists in the sporulated form, which can remain viable for several months. It is resistant to boiling and antiseptics but is killed by autoclaving at 121°C for 15 minutes. Clostridium tetani is not locally invasive and does not provoke an inflammatory response, and inoculation of spores into viable tissue does not produce tetanus. However, tissue necrosis, foreign bodies, or concurrent anaerobic or facultative anaerobic infections lower the normal oxidation-reduction potential of the tissue, which allows conversion to the vegetative form with subsequent toxin formation. The toxins produced include tetanolysin, which is capable of causing local damage to viable tissue, thereby optimizing conditions for bacterial multiplication, and production of tetanospasmin, which is a potent neurotoxin responsible for the clinical disease state.5 Toxin formed in a skin wound enters the underlying muscle and may spread to adjacent muscles. It then accumulates in the nerve endings of motor fibers. Retrograde transport of the toxin then occurs via intra-axonal and periaxonal pathways from nerve endings to the ventral horns of the spinal cord or motor nuclei of the cranial nerves. 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.6 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.

In the anterior horn or cranial nerve nuclei the toxin accumulates in the presynaptic apparatus, impairing spontaneous secretion and evoked release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and glycine.1,5 Because inhibitory synapses are more sensitive to the effects of tetanus toxin than excitatory synapses, impaired inhibition of motoneurons and interneurons results in enhanced excitation and muscular rigidity. Disruption of the inhibitory interneurons within the propriospinal connections results in enhanced excitation such that stimulation from the periphery, such as light touch or visual or auditory stimuli from the reticular formation, can result in the generalized spasms seen in tetanus.

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 inhibition.5

There are three clinical forms of tetanus: generalized, local, and cephalic. Generalized tetanus is the most common form and is characterized by diffuse muscle rigidity. Localized tetanus is characterized by rigidity of a group of muscles in close proximity to the site of injury. Cephalic tetanus, which is a variant of local tetanus, is defined as trismus plus paralysis of one or more cranial nerves.7Both local and cephalic tetanus may progress to generalized tetanus, the latter occurring in approximately 65% of cases.

The most common means by which C. tetani enters the human host is through lacerations, especially if associated with tissue necrosis or foreign body. Tetanus can also follow burns or animal bites, septic abortion complicated by gangrene of the uterus, and rarely after otherwise uncomplicated abdominal surgery.8 Untreated middle ear infections account for up to 30% of the cases of tetanus in India.9 Intravenous drug users can develop tetanus associated with skin infections caused by use of inadequately sterilized needles.10 However, in 15% to 25% of cases a portal of entry cannot be determined (cryptogenic tetanus).3,9,10

The interval between injury and onset of clinical symptoms is usually from 3 days to 3 weeks, but occasionally is as long as several months. Cephalic tetanus after scalp or facial injury tends to occur earlier with an incubation period of 1 day to 2 weeks.7 In general, the shorter the incubation period, the more severe the disease. However, a long incubation does not guarantee a mild attack.

Muscular rigidity is the most prominent early symptom of tetanus. Rigidity of the masseter muscle (trismus) results in difficulty with opening the mouth and chewing. Rigidity of the facial muscles gives the characteristic smile of tetanus (risus sardonicus). Opisthotonos is caused by rigidity of the vertebral muscles and antigravity muscles. Abdominal muscle rigidity may simulate peritonitis. Nuchal rigidity may simulate meningitis. In the Edmondson and Flowers series of 100 patients,3 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. In cephalic tetanus cranial nerve palsies may precede trismus.3,11

The period of onset of the disease is defined as the interval between the first symptom and the first generalized muscular spasm. A shorter period of onset is usually predictive of a severe attack.

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.12 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 have 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.13 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.14

A complete blood count will usually show a leukocytosis with a left shift, and less frequently, a lymphocytosis. Examination of urine may reveal proteinuria and leukocytes thought to result from accumulation of tetanus toxin in the kidneys.9 Other nonspecific laboratory abnormalities include elevation of serum transaminases, increased catecholamine levels in serum and urine, and decreased serum cholinesterase level. Creatine phosphokinase (CPK) is usually normal initially but generally rises with the onset of muscular spasms. Idoko and colleagues reported elevated cerebrospinal fluid (CSF) protein levels in 26 of 34 (76.5%) patients with tetanus.15 The elevation of CSF protein appeared to correlate with disease severity. Nineteen patients with severe disease (10 ultimately fatal) had significantly higher CSF protein values (mean = 1582 mg/L) than mild cases (mean = 400 mg/L).

Complications of tetanus are numerous and frequent. The need for long-term endotracheal intubation and ventilatory support coupled with increased risk of aspiration may result in bacterial pneumonia. Other nosocomial infections also occur, as many patients require a long-term stay in an ICU. These may include infections of vascular access catheters, catheter-related urosepsis, and infected decubitus ulcers. Protracted immobilization places the patient at risk for deep venous thrombosis and pulmonary thromboembolism, which is commonly reported as a cause of death.

The diagnosis of tetanus is based on clinical manifestations rather than laboratory tests. Tissue cultures are positive in less than 50% of patients.16 Since the organism is noninvasive, blood cultures are of little value except in diagnosing secondary infection. The major clinical features on which the diagnosis of tetanus is based are listed in Table 59-1 along with the features of other conditions with which it can be confused. Symptoms of strychnine poisoning usually begin 5 to 60 minutes after ingestion and resolve after 6 hours, although the hyperreflexia, stiffness, and muscle pains may last 3 to 7 days. The rapid course distinguishes strychnine poisoning and acute dystonic reactions from tetanus. Stiff-man syndrome is characterized by initially intermittent followed by continuous spasms of limb and trunk muscles that disappear during sleep. Trismus, facial palsy, nuchal rigidity, and continuous muscle rigidity are not seen in rabies. Cutaneous hyperesthesia is quite marked in rabies, as are disturbances in mentation, and both are absent in tetanus. Isolated paralysis of the facial nerve may be due to Bell palsy or an early manifestation of cephalic tetanus.9 Patients with meningitis have nuchal rigidity but not trismus. However, examination of CSF is mandatory if the diagnosis is uncertain. Determination of serum calcium will rule out hypocalcemic tetany. Unlike trismus owing to these processes, tetanic trismus becomes more pronounced as the jaw is forced open.9 Isolated trismus may be due to subluxation or arthritis of the temporomandibular joint or any inflammatory process involving teeth, mouth, tonsils, or pharynx.

Patients with a presumptive diagnosis of tetanus should be admitted to an ICU.3,16 Since the period of onset of the disease ranges from less than 1 to 12 days, even patients with mild tetanus (trismus, dysphagia, and localized rigidity) should be observed in an ICU for at least 1 week (2 weeks if no resolution of symptoms is noted). Patients with incubation periods of greater than 20 days who have only localized rigidity can be safely discharged to the ward after a few days of observation provided no progression of the disease has occurred.

The principles of initial treatment of tetanus consist of airway management, sedation, treatment of the portal of entry, antitoxin therapy, administration of appropriate antibiotics, and general supportive measures.3,5,9,16 Drugs commonly used in the management of tetanus are listed in Table 59-2 together with their indications and usual doses.

Appropriate management of the airway is the first priority. Patients with trismus and localized rigidity with no evidence of respiratory compromise do not require prophylactic endotracheal intubation. Patients with diffuse rigidity, especially if unresponsive to benzodiazepine therapy, should be intubated, even in the absence of respiratory compromise. Intubation should be performed in all patients who have already had a generalized spasm or in any patient with evidence of respiratory compromise, including patients with severe dysphagia who are in danger of aspiration. The preferred route (nasotracheal vs. orotracheal) and method (awake vs. anesthetized) of intubation depends on the clinical situation. Ideally an anesthesiologist should perform intubation. An emergency cricothyrotomy tray should be at the bedside prior to attempted intubation. If paralysis is required to facilitate intubation, a nondepolarizing agent should be used, since depolarizing neuromuscular blocking agents (e.g., succinylcholine) may cause hyperkalemia and cardiac arrest in patients withbreak tetanus.17

The classical approach for patients with muscular rigidity is sedation with intravenous benzodiazepines and narcotics. The doses should be titrated to reduce rigidity and provide adequate analgesia, respectively. Intubation, ventilation, sedation, and neuromuscular blockers3,9,16,18 are the conventional therapies for tetanic spasms. However, in the early 1990s case reports suggested that neuromuscular blockade and ventilation could be avoided by using dantrolene and sedation.19,20 More recently Attygalle and Rodrigo published their experience with 40 patients using intravenous magnesium as a first-line therapy for rigidity, spasms, and control of autonomic dysfunction.21 In 95% of patients, control of spasms and muscle rigidity was achieved with serum magnesium levels of 2.0 to 4.0 mmol/L. The authors published their specific treatment protocol and stressed the importance of early tracheostomy for tracheal toilet. If neuromuscular blockade is required, pancuronium,9atracurium,22 and vecuronium18 have been reported as being safe and effective. Vecuronium has no cardiovascular side effects, which may be advantageous in treating patients with autonomic dysfunction.18

Aggressive surgical treatment of tetanus-producing wounds results in improved survival. The wound should be excised with a 2-cm margin.23 If gangrene is present, the extremity should be amputated at least one uninvolved joint proximal to the wound.23 The decision to perform a hysterectomy on a patient who develops tetanus following induced abortion or in the postpartum period should be based on the presence of associated invasive bacterial sepsis, gangrene of the uterus, or uterine injury. Tetanus is not itself an indication for hysterectomy.9

Several studies comparing mortality rates of patients with tetanus treated with and without antitoxin have produced conflicting results. However, the importance of answering this question has been markedly reduced by the availability of human tetanus immune globulin (HTIG), which has no serious adverse effects. It is now generally agreed that patients with tetanus should be treated with antitoxin as soon as possible.1,5,16 However, controversy persists regarding the preferred route and dosage of antitoxin. There is evidence that in patients who have not yet progressed to generalized rigidity and spasms or those with very mild disease, intrathecal HTIG may reduce length of stay, prevent generalization, and in one study reduced mortality.24,25 Conversely, once generalization has occurred, the administration of intrathecal HTIG has failed to improve survival. Intramuscular doses of HTIG ranging from 3000 to 6000 IU have been suggested.5,16 It is important to administer antitoxin prior to débridement because the toxin may be introduced into the bloodstream during manipulation.16

Antibiotics are generally given both to treat infection at the injury site and to eliminate continued toxin production. Metronidazole 500 mg intravenously every 6 hours for 10 days is the antibiotic of first choice for C. tetani.26 Penicillin G, tetracycline, erythromycin, clindamycin, and chloramphenicol are also effective.5,26 Penicillin is a GABA antagonist. Given the pathophysiology of tetanus, the use of GABA antagonists is concerning.

General supportive measures include establishing intravenous access to maintain adequate fluid and electrolyte balance. A Foley catheter should be inserted in all but the mildest cases to prevent urinary retention. Appropriate prophylaxis for stress ulcers is indicated. Ideally, intubated patients should be fed using the nasojejunal route to minimize the possibility of aspiration. Energy expenditure in patients with severe tetanus receiving appropriate sedation are within 10.5% of predicted basal metabolic rates using the Harris-Benedict equation.27 Subcutaneous heparin is given to prevent deep venous thrombosis. Physiotherapy prevents contractures in patients treated with neuromuscular blockers.

Arterial and pulmonary artery catheterization may be useful to manage the autonomic dysfunction of severe tetanus. In the absence of cardiac disease the cardiac index tends to be elevated. Rapid changes in systemic vascular resistance are responsible for fluctuations in blood pressure.5 The pulmonary capillary wedge pressure and central venous pressure are usually normal, but may be low in patients with severe spasms and diaphoresis, which have led to hypovolemia. It is important to ensure that hypovolemia is promptly corrected, since this will substantially increase the potential for immediately life-threatening hypotension in the presence of the autonomic instability. Core body temperature should be monitored and hyperpyrexia (core temperature greater than 41°C) avoided owing to the increased risk of sudden death.28 Treatment of cardiovascular instability consists of deep sedation, which if unsuccessful is followed by high-dose magnesium sulfate infusions.29–31 Continuous benzodiazepine intravenous infusion should be tried initially, followed by continuous narcotic infusion if required. Successful control of autonomic dysfunction has been achieved using a bolus (5.0 μg/kg IV) plus a continuous infusion (4.0 to 6.0 μg/kg per hour IV) of fentanyl when a benzodiazepine alone was insufficient.30 Patients unresponsive to deep sedation have been successfully treated with intravenous magnesium sulfate. A loading dose of 70 mg/kg IV over 5 minutes is followed by a continuous infusion titrated to maintain serum magnesium levels between 2.5 and 4.0 mmol/L.29 This usually requires infusion rates of 1 to 3 g/h. Serum calcium and magnesium levels should be measured every 4 hours.31 Calcium supplements may be required to maintain serum calcium levels above 6.8 mg/dL (1.7 mmol/L).29 Any magnesium-induced cardiac arrhythmias should also be treated with IV calcium and the infusion rate of magnesium should be reduced. There is conflicting opinion regarding the ability to reduce sedation and/or analgesic medications in patients who respond to intravenous magnesium therapy.29,31 Autonomic dysfunction unresponsive or incompletely responsive to magnesium may respond to clonidine.32,33 Continuous epidural infusion of bupivacaine and sufentanil was retrospectively evaluated in 11 patients with severe tetanus and autonomic dysfunction.34 In two patients the epidural alone was ineffective, therefore morphine, muscle relaxation, and phenobarbitone or chlorpromazine were added. One patient developed an epidural abscess requiring a laminectomy with surgical drainage. The authors discuss in detail the risks of placing epidural catheters in patients with tetanus and suggest a caution for advocates of intrathecal therapy. In the past, β-blockers have been used. However, there is now evidence that their use is associated with a significant risk of death due to cardiac arrest,14,35–37 and they are no longer recommended.

With modern intensive care management, mortality ranges from 10% to 15% overall and is no longer influenced by age.5,38 In areas where such care is not available, mortality rates of between 25% and 50% are usual.1,3,5,39 The general quality of critical care support is likely a key determinant of prognosis. In a recent study tracking mortality from severe tetanus in Brazil over two decades, mortality fell from 36.5% in the early time frame to 18.0% in the later period, likely related to general advances in ICU management.40

Finally, it is important to remember that recovery from tetanus does not guarantee natural immunity.1 Patients should begin their primary immunization series prior to leaving the hospital; indeed, since passive immunization with HTIG does not interfere with successful active immunization, the series can begin even before the patient leaves the ICU.