Tetanus

The objectives of the study were to describe a novel presentation of tetanus and to review the course of the respiratory component and the treatment and management of the disease. A case report is presented with a review of a 25-year experience at Mayo Clinic. We describe the case of a 65-year-old woman who presented with persistent hiccups, dyspnea, and pleurisy of 3 days duration that was caused by tetanus from inadequate secondary immunity. She required intubation for progressive trismus and laryngospasm-associated respiratory failure. Infusion of lorazepam did not control her spasms. Refractory spasms and hiccups resolved with fentanyl and cisatracurium therapy. After 3 weeks, the patient was weaned from the ventilator with complete recovery. In the past 25 years, nine additional patients have presented to Mayo Clinic with acute tetanus. Respiratory failure requiring intubation developed in seven patients, and six of the seven intubated patients survived with minimal deficits. The prognosis of tetanus is favorable if it is diagnosed promptly and if treatment and supportive measures are begun. To our knowledge, this is the first report of a patient with acute tetanus presenting with hiccups. This report also confirms the results of previous studies that suggested a need for improved immunity in the elderly population.

Key words: respiratory; respiratory failure; tetanus

Abbreviations: GABA = [gamma]-aminobutyric acid; TIG = tetanus immune globulin

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Tetanus remains a major worldwide health problem. We report a novel case with a patient presenting with the clinical symptom of hiccups. Early diagnosis is necessary to avoid complications and to institute supportive care. A review of the Mayo Clinic experience suggests that early management, with mechanical ventilation if necessary, is associated with a good prognosis and functional recovery. In addition, this report confirms the results of previous studies that suggested a need for improved immunity in the elderly population.

CASE REPORT

A 65-year-old woman presented to the emergency department with hiccups, dyspnea, pleurisy, jaw stiffness, and epigastric pain of 3 days' duration. She had been seen 1 week earlier for a traumatic knee laceration, which was irrigated and sutured. She was given a tetanus toxoid vaccination as part of her care. Four days after the initial injury, she underwent wound incision and drainage and began therapy with cephalexin.

Evaluation results at the local hospital included a normal ECG and normal levels of cardiac enzymes. Treatment with cephalexin was continued because of purulence and erythema at the wound site. The patient underwent chest CT angiography, mid file findings demonstrated no evidence of pulmonary embolism. The patient was subsequently transferred to our hospital for further treatment.

At the time of transfer, the patient was afebrile, normotensive, tachycardic (110 beats/min) and tachypneic (30 breaths/min). Oxygen saturation of arterial blood measured by pulse oximetry was 93% with the patient breathing room air. She appeared uncomfortable, anxious, and diaphoretic with pleuritic and abdominal pain. Her neck was stiff, and she could open her jaw approximately 2 cm. She had hiccups and moderate, generalized rigidity of the abdominal muscles. Mild erythema, edema, tenderness, and purulent discharge surrounded a 4-cm laceration of the right knee. Laboratory data included an elevated WBC count of 15.4 x [10.sup.3] cells/[micro]L and a sodium concentration of 128 mEq/L. The other laboratory data were normal. Initial pH, PaC[O.sub.2], and Pa[O.sub.2] were 7.40, 38 mm Hg, and 75 mm Hg, respectively, with the patient breathing supplemental oxygen of 2 L/min through a nasal cannula. The levels of cardiac enzymes were normal. Electrocardiography revealed sinus tachycardia. A chest radiograph was normal. A lower-extremity Doppler duplex ultrasonographic evaluation, repeat chest CT angiography, and a pulmonary angiogram did not demonstrate deep venous thrombosis or pulmonary embolism. A CT scan of the head and neck demonstrated no evidence of cervical spine fracture or intracranial abnormality. Therapy with cephalexin was discontinued, and therapy with cefazolin was started.

The patient's clinical course was notable for abdominal spasms provoked by light, sound, or touch that eventually involved the chest wall, causing episodic respiratory distress and oxygen desaturation to < 70%. The patient was given tetanus immune globulin (TIG), 3,000 IU IM. She was transferred to the medical ICU. On arrival, she was unable to speak because of generalized muscle rigidity, including the muscles of the face, jaw, and neck. The patient was bronchoscopically intubated, and mechanical ventilation was instituted. Metronidazole therapy was started (500 mg IV every 6 h), Infusion of lorazepam, 5 mg/h titrated up to 15 mg/h, was initiated to control spasms, but the spasms continued. A fentanyl infusion was begun to control the pain caused by the muscle spasms. Pain was assessed, and the fentanyl dose was adjusted on the basis of a subjective bedside evaluation by medical and nursing staff who used direct patient feedback and a score of < 3 on a nonstandardized analog scale of 1 to 10. Fentanyl dosages ranged from 50 to 125 [micro]g/h. Neuromuscular blockade with cisatracurium was subsequently instituted. Sutures were removed from the knee laceration, and the wound was debrided. A culture of the laceration swab grew coagulase-negative Staphylococcus. Synovial aspiration of the right knee yielded no organisms. A urine drug screen was negative for neuroleptic agents and strychnine.

The patient's initial course during the first weeks was characterized by nonsustained episodes of tachycardia and hypotension. Use of the paralytic agent was halted daily to assess for the resolution of the spasms. Therapy with empiric dantrolene, 100 mg three times daily, and baclofen, 15 mg twice daily, was begun to hasten the cessation of therapy with cisatracurium and lorazepam. On the 12th day after ICU admission, a tracheostomy was performed. Three weeks after ICU admission, the patient demonstrated a decrease in autonomic instability, muscle rigidity, and spasms, prompting discontinuation of the neuromuscular blockade medication. She was subsequently weaned from the ventilator. Physical therapy progressed successfully. By day 46, the patient was able to walk short distances with assistance and was transferred to the physical medicine and rehabilitation center where she recovered completely.

MAYO CLINIC EXPERIENCE

In the past 25 years, nine additional patients have presented to the Mayo Clinic with acute tetanus (Table 1). The majority of the patients were elderly (average age, 68 years) and had received childhood vaccinations only or did not know their vaccination status. Most patients presented with mild early trismus (78%), which led to generalized tetanus. The treatment of these patients is described in Table 2. Respiratory failure requiring intubation developed in seven of these patients (78%). Six of the seven intubated patients survived with minimal deficits. One patient died early in the course of the disease because of a large anterolateral myocardial infarction.

DISCUSSION

Significant Findings

A novel finding in this case report is the presenting symptom of hiccups. In addition, this report confirms previous reports that elderly patients may not have adequate immunity to prevent the illness. Finally, this case and the Mayo Clinic experience demonstrate the need for prompt diagnosis and treatment because of the risk of respiratory failure.

General Description

Tetanus is caused by a toxin secreted by Clostridium tetani, a Gram-positive, obligate anaerobic bacillus that forms a stable terminal spore. C tetani and its spores are ubiquitous in nature, and are found in the soil and in the intestines and feces of domestic animals and humans. The spores are resilient to moisture, to some chemical disinfectants, and to variations in temperature, including boiling. (1,2)

The spores are noninvasive, and inoculation usually requires a disruption of the skin barrier by a foreign body. (2) The insult to the skin barrier typically follows a deep penetrating wound. However, minor trauma has caused up to 30% of infections in previous reports (3) as well as in our case series, with many patients presenting with minor injuries or disruption of the skin harrier by other disease mechanisms. In addition, a number of reported cases have not been associated with an identifiable source. (4) The time between inoculation and clinical manifestation varies, reflecting the distance required for the toxin to ascend and interact with the CNS. (1) The early onset of symptoms (ie, < 48 h) typically correlates with more severe disease. (1,2,5-7) In most instances, clinical symptoms occur within 7 to 14 days after inoculation, although cases also have occurred almost 9 months after the injury. (4)

C tetani secretes two toxins, tetanospasmin and tetanolysin. Although the organism remains within the local environment of the injury, the tetanospasmin toxin travels to the neuromuscular junction by intra-axonal transport within the CNS. (6,7) At the synaptic junction of inhibitory nerves, the toxin prevents the release of [gamma]-aminobutyric acid (GABA). Without GABA, there is no inhibitory control to prevent sustained excitatory nervous discharges, leading to the clinical manifestations of tetanus. The role of tetanolysin is not fully understood. Within our patient population, the location of the injury, in particular the distance from the CNS, did not correlate with the onset of symptoms.

Clinical Manifestations

The manifestations of tetanus can be either local or general. Generalized tetanus is the most common form, with the patient presenting with pain, headache, muscle rigidity (including trismus, risus sardonicus, and opisthotonos), generalized spasms, and autonomic instability. Trismus is often the presenting symptom. (1) Within our total patient population, trismus developed in 8 of the 10 patients (80%) before presentation. Progression of the disease may lead to laryngeal obstruction and a reduction in chest wall compliance, causing respiratory failure. Respiratory failure is the most common direct cause of death from tetanus worldwide. (1) Manifestations of autonomic instability are diverse, including hypertension or hypotension, diaphoresis, cardiac arrhythmias, and hypermetabolism. Hypotension and tachycardia complicated the course of the disease in our patient. Increased urine and plasma catecholamine levels also reflect sympathetic overactivity. (5,8-10) In contrast, localized tetanus is less severe, and is characterized by rigidity and pain confined to the muscles adjacent to the wound. (7) In our patient, the hiccups most likely resulted from underlying diaphragmatic spasms. With progression of the disease, these muscle spasms involved the chest wall and subsequently spread throughout her body.

The course of the disease is typically prolonged, requiring weeks to months of supportive management to resolve. The spasms and autonomic instability are usually most prominent in the first few weeks, peaking near the second week and then resolving. However, the muscular rigidity may persist for several months. (1,2,5)

Recognizing the clinical symptoms is essential in making the diagnosis of tetanus. Laboratory tests usually are beneficial in riding out other diseases rather than in eon firming tetanus, Wound cultures, which are positive for C tetani in only 30% of documented cases, have limited value. (5) The differential diagnosis for an adult includes strychnine poisoning, orofacial infection or trauma, rabies, and drug-induced dystonic reaction. (1)

Disease Management

Management of the disease requires the prevention of tetanospasmin absorption, treatment of symptoms, stabilization of autonomic instability, antibiotic therapy, and control of the airway with assisted ventilation if indicated.

To prevent further absorption of tetanospasmin, the patient should receive human TIG. For acute disease, TIG directly neutralizes free tetanospasmin, theoretically resulting in less absorption. Tetanus toxoid also may be of value by stimulating autoantibody production. However, this effect is typically delayed and may not confer added benefit.

The management of symptoms includes sedation, pain management, and muscle relaxation. Benzodiazepines, which are GABA agonists, are considered to be the initial standard therapy for both sedation and muscle relaxation. (2) Additional opioids may be necessary for pain control, sedation, and muscle relaxation to replace endogenous depleted opioids. (11,12) Baclofen, a specific GABA(B) agonist, has been used in the treatment of muscle spasms in tetanus, however, the inability of baclofen to cross the blood-brain barrier and the oral formulation of baclofen may limit its use. (2,13,14) Dantrolene, a direct skeletal muscle relaxant, also has been shown to be effective in the short-term and long-term management of muscular rigidity and spasticity. (15-17) Agents such as vecuronium or pancuronium may be used in patients who require mechanical ventilation. (18) Vecuronium and cisatracurium have been considered to be the agents of choice because of the low overall incidence of cardiac effects in patients with tetanus who are at risk of autonomic instability. (19)

Autonomic instability is variable, and treatment may differ in individual cases. Generally, an excess of catecholamines characterizes the state. Previous studies (2,11,12,20,21) have reported successful management with magnesium sulfate, atropine, benzodiazepines, morphine, [alpha]-blockers, and [beta]-blockers in controlling sympathetic nervous system overactivity.

Antibiotic therapy reduces mortality and the need for muscle relaxants. (22,23) The disease may, however, be exacerbated by increased activity in the CNS. Given the increased risk of convulsions that has been observed with high doses of penicillin in animal models, (1,2,5,7) metronidazole is the drug of choice. In addition, compared with penicillin, metronidazole reduces mortality and shortens hospital stays. (23)

Because respiratory failure is the most common cause of death, early protection of the airway is essential. In our case series, the majority of patients developed generalized tetanus and required ventilation. No studies have evaluated different modes of ventilation on the outcome and management of tetanus. Tracheostomy may be indicated for patients who require prolonged ventilation until the muscular rigidity resolves and respiratory muscle function improves. Patients with severe disease in whom a prolonged course of ventilation is expected may benefit from early tracheostomy to reduce unnecessary stimuli. (1,2)

Prevention

Despite efforts by the World Health Organization to eradicate the disease, tetanus remains a worldwide cause of morbidity and mortality. Approximately 800,000 to 1 million deaths from tetanus occur each year, with approximately 40% occurring in the neonatal population. (24) Within the United States, the majority of cases are elderly adults with inadequate immunity (ie, tetanus antibody titer of < 0.015 IU/mL). (25-28) Alagappan et al (25) reported in a study of 129 elderly patients that 50% of the total study population had inadequate immunity (57% women; 27% men). Wesche and Overfield (26) studied 225 blood donors who were > 50 years of age and found that only 14% had adequate protective levels of antibodies. Furthermore, they found that low levels of protective antibodies were independent of previous childhood immunization. (26,27) In a large study of 13,714 patients, Gergen et al (28) found that 80% of patients aged 6 to 39 years had protective immunity to tetanus. The prevalence of immunity decreased sharply with age to 28% in patients [greater than or equal to] 70 years of age. Variables associated with lower rates of immunity included poverty, low educational status, birth outside the United States, and women without a history of military service. (28) The experience at Mayo Clinic confirms these reports that elderly patients may not have adequate immunity and are therefore more susceptible to the disease and its complications.

Morbidity and mortality are high among elderly patients with the disease. The case-fatality rate increases with age, reaching 50% in patients > 60 years of age. (3,39,) Elderly patients account for 75% of the tetanus deaths in the United States. (1,3,29) However, the review of our clinical experience suggests that early recognition, treatment, and aggressive supportive care may dramatically reduce both mortality and morbidity in the elderly population. The current recommendation by the Committee of Immunization Practices, (30) which is supported by initiatives from the American College of Physicians-American Society of Internal Medicine, (31) is to give adults a tetanus booster every 10 years. However, this recommendation is controversial because a previous study (32) suggested that adults require a booster every 20 years to retain adequate immunity. Nonetheless, the evidence demonstrates that many adults, especially elderly adults, within the United States do not have adequate immunity. Efforts must be made to provide tetanus toxoid booster vaccinations to adults to reduce the overall prevalence and associated morbidity of this disease.

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* From the Department of Internal Medicine (Drs. Bunch and Thalji), Division of Cardiovascular Diseases (Dr. Pellikka), and the Division of Pulmonary and Critical Care Medicine and Internal Medicine (Dr. Aksamit), Mayo Clinic, Rochester, MN.

Manuscript received December 13, 2001; revision accepted May 14, 2002.

Correspondence to: Timothy R. Aksamit, MD, FCCP, Division of Pulmonary and Crit Care Med and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: Aksamit. Timothy@Mayo.Edu

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