Tetanus

1. General Overview

Tetanus is a severe acute disease with a potentially fatal outcome caused by the toxin of Clostridium tetani, characterized by convulsive spasms occurring on a background of increased muscle tone.

Tetanus is preventable by vaccination, and neonatal tetanus can be prevented by maternal immunization during pregnancy.

2. Causative Agent

Structural characteristics of Clostridium tetani

• Clostridium tetani (C. tetani) is a Gram-positive, obligate anaerobic, slender rod-shaped bacillus that is motile and spore-forming.
• Dimensions: approximately 0.5–2.5 µm in length and 0.3–0.5 µm in width. Under unfavorable conditions, a terminal round spore forms at one end, giving the organism a characteristic drumstick appearance. C. tetani is motile by means of numerous flagella.
• Genome: consists of approximately 2.8 million nucleotide base pairs encoding more than 2,300 proteins.
• C. tetani produces two exotoxins: tetanolysin and tetanospasmin. Tetanospasmin consists of two polypeptide chains: a heavy chain (100 kDa) and a light chain (50 kDa) linked by a disulfide bond. The light chain has endopeptidase activity, blocks neurotransmitter release, and causes muscle rigidity. By weight, tetanospasmin is one of the most potent toxins known. The minimum lethal dose in humans is estimated at 2.5 nanograms per kilogram of body weight, or 175 nanograms for a 70-kg individual.

C. tetani is sensitive to heat and cannot survive in an oxygen-rich environment. In contrast, its spores are highly resistant to heat and common disinfectants. They can survive in an autoclave at 121°C for 10–15 minutes. Tetanus spores are also relatively resistant to phenol and other chemicals. They are widely distributed in soil and are present in the intestines and feces of many animals. Soil fertilized with manure may contain large numbers of spores. Spores may also be found on the skin surface.

Figure 1. Morphology of C. tetani.

3. Epidemiology

Source of infection

C. tetani is found mainly in soil and in the intestinal tract and feces of many animal species.

Mode of transmission

Transmission occurs through contaminated wounds, which may be open or closed, large or small. Tetanus may occur after elective surgery, burns, deep puncture wounds, crush injuries, otitis media, dental caries, animal bites, miscarriage, abortion, and childbirth.

Disease distribution

Tetanus occurs worldwide, but it is most common in densely populated regions with hot and humid climates. An estimated 213,000–293,000 deaths from tetanus occur globally each year.

4. Pathogenesis

C. tetani enters the body through a wound. In healthy, oxygen-rich tissues, spores cannot germinate and are destroyed by macrophages. Under anaerobic conditions, spores germinate, allowing the bacteria to revert to the vegetative state and proliferate. Toxins are produced and enter the nervous system either from adjacent muscles or by dissemination to distant sites via the bloodstream and lymphatics. The toxins act at multiple sites within the central nervous system.

The characteristic clinical manifestations of tetanus develop when tetanus toxin interferes with neurotransmitter release, thereby blocking inhibitory impulses. The toxin acts as a presynaptic inhibitor at multiple neural sites, including neuromuscular junctions. This results in rigidity and spasms of opposing muscle groups. Muscle groups supplied by the shortest nerve pathways are affected first; therefore, trismus and dysphagia are often the earliest symptoms.

Loss of autonomic inhibition may also occur, leading to uncontrolled sympathetic and parasympathetic dysfunction. Tetanus toxin may enter adjacent neurons and spread throughout the central nervous system, resulting in thermoregulatory, respiratory, and cardiovascular disturbances seen in severe cases.

5. Clinical Manifestations

Incubation period

The incubation period is defined as the interval from the occurrence of the wound to the appearance of the first symptom of tetanus, usually trismus. It may range from 2 days to 2 months, although most cases occur within 8 days. A shorter incubation period (<7 days) is associated with more severe disease.

Onset period

This period extends from the onset of trismus to the first generalized convulsion or the first pharyngeal/laryngeal spasm, usually lasting 1–7 days. A shorter onset period (<48 hours) is associated with more severe disease.

The earliest symptom is trismus: initially, patients experience jaw fatigue, dysarthria, difficulty swallowing, impaired mastication, and progressively worsening inability to open the mouth. When the mandible is depressed with a tongue depressor, the jaw clenches even more tightly (trismus sign). This sign is present in all patients.

Rigidity of other muscle groups

• Facial muscle rigidity produces the characteristic tetanic facies or risus sardonicus (prominent forehead wrinkles, furrowed brows, and deepened nasolabial folds). Rigidity of the posterior cervical muscles leads to neck stiffness and progressive hyperextension, with prominent sternocleidomastoid muscles.
• Rigidity of the back muscles produces opisthotonos or extreme spinal extension. Abdominal muscle rigidity causes the rectus muscles to become prominent, and the abdomen feels board-like on palpation.
• Rigidity of the thoracic and intercostal muscles restricts chest wall movement.
• Rigidity of the upper limbs causes flexed arm posture, whereas rigidity of the lower limbs produces extension posture.
• External stimulation intensifies the spasms and causes severe pain.

Other manifestations may include agitation, high fever, profuse sweating, and tachycardia.

Fully developed stage

This stage extends from the first generalized convulsion or pharyngeal/laryngeal spasm until the beginning of recovery, usually lasting 1–3 weeks. Clinical features include:

• Continuous generalized muscle rigidity, worsened by stimulation, with severe pain; typical rigidity may cause marked opisthotonos.
• Laryngeal spasm causing dyspnea, cyanosis, asphyxia, and cardiac arrest.
• Pharyngeal spasm causing dysphagia, impaired swallowing, pooling of secretions, and a high risk of aspiration.
• Spasm of sphincter muscles causing urinary retention and constipation.
• Generalized convulsions superimposed on a rigid muscular background, occurring spontaneously or intensified by external stimuli. During convulsions, the patient remains conscious and typically exhibits clenched fists, backward arching of the spine, abducted or flexed upper limbs, and extended lower limbs. Apnea frequently occurs during these postures. Convulsions may last from a few seconds to several minutes or longer. During these episodes, laryngeal spasm and rigidity of respiratory muscles can easily lead to hypoventilation, hypoxemia, cyanosis, apnea, and death.

Autonomic dysfunction occurs in severe cases and may include pallor, profuse sweating, excessive salivary and bronchial secretions, fever of 39–40°C or higher, hypertension or hypotension, labile blood pressure, cardiac arrhythmias, and cardiac arrest.

Recovery stage

The recovery stage begins when generalized convulsions and pharyngeal/laryngeal spasms become less frequent; generalized rigidity persists but gradually decreases; the mouth can be opened progressively wider; and the swallowing reflex gradually returns. This stage may last from several weeks to several months depending on disease severity.

6. Laboratory Investigations

• Measurement of serum antibody levels against tetanus toxin.
• Culture of C. tetani from the wound and assessment of toxigenicity. However, results are often delayed, and a negative culture does not exclude the diagnosis.
• Laboratory abnormalities related to wound infection and complications of tetanus may also be observed.

7. Clinical Classification

• Generalized tetanus: the classic form, with the four clinical stages described above.
• Localized tetanus: rare, characterized by rigidity, hypertonia, and spasms confined to one limb or one region of the body; it often progresses to generalized tetanus.
• Cephalic tetanus: occurs in patients with wounds of the head, face, or neck; manifestations include trismus, dysarthria, dysphagia, facial muscle rigidity, and seventh cranial nerve palsy. It often later progresses to generalized tetanus.
• Neonatal tetanus: classically occurs in infants aged 3–28 days (mean 8 days), with an incubation period ranging from 2 days to more than 1 month. Initial symptoms are poor feeding and weak crying, followed by trismus, inability to suck, generalized muscle rigidity, and convulsions.

8. Complications

Respiratory complications

• Pharyngeal and laryngeal spasm causing asphyxia, apnea, aspiration, and reflux of gastric contents into the lungs.
• Retention of respiratory secretions due to hypersecretion, inability to swallow, and weak cough reflex.
• Respiratory failure caused by prolonged convulsions or prolonged use of high-dose sedative anticonvulsants.

Cardiovascular complications

• Tachycardia and tachyarrhythmias associated with convulsions, high fever, autonomic dysfunction, and respiratory failure.
• Circulatory collapse and hypotension due to autonomic dysfunction, fluid depletion, and sedative adverse effects. Blood pressure may fluctuate markedly because of autonomic instability.
• Sudden cardiac arrest due to respiratory failure, autonomic dysfunction, and possibly the effect of tetanus toxin itself.

Gastrointestinal complications

Abdominal distension due to decreased intestinal motility, impaired absorption, and constipation; stress-related gastric ulceration and gastrointestinal bleeding.

Infectious complications

Bronchitis, pneumonia, infection at the tracheostomy site, phlebitis at intravenous access sites, urinary tract infection, sepsis, sinusitis, and others.

Fluid and electrolyte imbalance

Disturbances in water and electrolyte homeostasis may occur.

Renal failure

When renal failure develops, the prognosis is very poor and the risk of death is high.

Other complications

Malnutrition, joint stiffness, pressure ulcers, impaired consciousness due to prolonged hypoxia, tongue laceration due to biting, and tooth fracture.

9. Treatment

Principles of treatment

Patients with tetanus should be managed in an intensive care unit. The treatment principles are:

• - Prevent further toxin production
• - Neutralize circulating toxin
• - Control spasms and muscle rigidity
• - Correct autonomic dysfunction
• - Provide intensive supportive care and other adjunctive measures

Specific treatment

Prevention of toxin production

Wound management: the wound should be widely opened and all necrotic tissue thoroughly debrided to eliminate tetanus spores.

Antibiotic therapy: metronidazole 500 mg intravenously every 6–8 hours, or penicillin G 1–2 million units intravenously every 4–6 hours. Erythromycin, penicillin V, or clindamycin may be used as alternatives to metronidazole and penicillin G. The treatment duration is 7–10 days.

Neutralization of tetanus toxin

Human tetanus immune globulin (HTIG): 3,000–6,000 units intramuscularly; or equine tetanus antitoxin serum (SAT): 1,500 units per ampoule, administered as a single dose of 400–500 units/kg body weight intramuscularly (adults usually receive 14 ampoules). SAT requires skin testing before administration, using 75 units for the test dose; HTIG does not require testing. In neonatal tetanus, SAT is administered at 1,000 units/kg body weight.

Control of spasms and muscle rigidity

General principles:

• The patient should be cared for in a quiet environment, with control of light and noise and avoidance of stimuli that may precipitate spasms.
• The minimum effective drug dose should be used to control spasms without causing respiratory or circulatory depression.
• Preference should be given to drugs with low toxicity, low addictive potential, rapid elimination, and good tolerance when administered orally or intravenously.
• Doses should be adjusted daily or even hourly as needed.
• Medications should be evenly distributed throughout the day as baseline therapy, with additional doses given when necessary.

Specific agents:

• Diazepam: usual dose 2–7 mg/kg/24 hours, divided every 1, 2, or 4 hours. It may be given orally via nasogastric tube or intravenously, 10–20 mg per dose, or by a combination of both routes. The total daily dose should not exceed 240 mg. High doses require ventilatory support.
• Lytic cocktail: 25 mg chlorpromazine + 50 mg promethazine (or 10 mg diphenhydramine) + 100 mg pethidine. Mixed and administered intramuscularly, from half to one full dose each time, not exceeding 3 doses/day and not for more than 1 week. It should not be used in children or pregnant women.
• Thiopental: indicated when benzodiazepines at maximal doses fail to control spasms. One to two grams are diluted in 250–500 mL of 0.9% sodium chloride or 5% glucose solution. Rapid infusion is given through a central venous catheter during spasms and stopped immediately once spasms cease. Continuous intravenous infusion up to 3.75 mg/kg/hour may be used. Mechanical ventilation and preferably tracheostomy are required when thiopental is used. Caution is advised when the total daily dose exceeds 4 g.
• Neuromuscular blocking agents: indicated when sedatives alone fail to control spasms and rigidity. Pancuronium may worsen autonomic dysfunction due to inhibition of catecholamine reuptake. Vecuronium is associated with fewer autonomic side effects. Pipecuronium may be used at 0.02–0.08 mg/kg/hour by intravenous infusion; it provides potent muscle relaxation with a prolonged duration of 1.5–3 hours and good cardiovascular stability.

Correction of autonomic dysfunction

• Magnesium sulfate: loading dose 40 mg/kg over 30 minutes, followed by maintenance infusion of 20–80 mg/kg/hour intravenously, aiming for a serum magnesium concentration of 2–4 mmol/L.
• Beta-adrenergic blockers: labetalol at 0.25–1.0 mg/min is commonly used; propranolol should be avoided because of the risk of sudden death.
• Morphine sulfate: used for analgesia and control of autonomic dysfunction, with continuous intravenous infusion up to 0.5–1.0 mg/kg/hour in severe cases.
• Atropine and clonidine: may be used to regulate heart rate and blood pressure, although their efficacy is limited.
• Deep sedation/anesthesia: combination of high-dose midazolam, thiopental, propofol, and fentanyl (continuous intravenous infusion 0.7–10 µg/kg/hour) or sufentanil (0.9–1.6 µg/kg/hour).

Intensive supportive care and other supportive measures

• Respiratory support: maintain airway patency by suctioning secretions; avoid oral feeding to prevent aspiration and glottic spasm; tracheostomy may be required for airway protection, secretion clearance, and mechanical ventilation.
• Circulatory support: maintain intravascular volume with fluids and use vasopressors and anesthetic agents when autonomic dysfunction causes labile blood pressure.
• Pyridoxine (vitamin B6): may increase GABA secretion and indirectly counteract the effect of tetanus toxin, which reduces GABA release. It is given orally at 10 mg/kg/day for 10–14 days; neonates receive 100 mg/day.
• Stress ulcer prophylaxis: with acid-suppressive therapy.
• Other supportive measures: maintain fluid and electrolyte balance; provide high-calorie nutritional support (70 kcal/kg/day); prevent constipation with laxatives; insert a urinary catheter early in cases of urinary retention; maintain hygiene of the body and natural orifices; reposition the patient to prevent pressure ulcers; perform frequent eye cleansing and instillation of ophthalmic drops; prevent venous thrombosis; initiate physiotherapy early once spasms have resolved; and use muscle relaxants as needed.

10. Prevention

Active immunization after recovery from tetanus

Immunity following tetanus infection is not durable; therefore, tetanus vaccination (tetanus anatoxin/toxoid) is required after recovery. A 3-dose schedule is recommended: the second dose 1 month after the first, and the third dose 6 months to 1 year after the second. Thereafter, a booster dose should be given every 5–10 years.

Passive prophylaxis after injury

The wound should be thoroughly debrided, irrigated with hydrogen peroxide and antiseptic solutions, and treated with penicillin or erythromycin. In individuals who have not been vaccinated or have been incompletely vaccinated against tetanus, SAT 1,500 units (1–2 intramuscular ampoules) should be administered, together with tetanus vaccine to establish active immunity.

Tetanus vaccines

DTP vaccine (diphtheria, tetanus, pertussis) is the vaccine of choice for children from 6 weeks to 6 years of age. The primary schedule includes doses at 2, 4, and 6 months of age, with an additional dose at 15–18 months. The first three doses are given at least 4 weeks apart; the fourth dose must be given at least 6 months after the third dose and not before 12 months of age. If the fourth dose is given before 4 years of age, a booster (fifth dose) is required at 4–6 years. If the fourth dose is given after 4 years of age, the fifth dose is unnecessary.

For individuals aged 7 years and older who have not been vaccinated, Td vaccine is recommended. The primary schedule includes 3 doses, with the first two doses at least 4 weeks apart and the third dose given 6–12 months after the second. Thereafter, a booster dose is administered every 10 years.

There is no maximum interval between tetanus vaccine doses.

Some modern combination vaccines also contain tetanus components, such as 6-in-1 vaccines (Infanrix Hexa, Hexaxim) and 5-in-1 vaccines (Pentaxim, ComBE Five).

REFERENCES

1. Disease factsheet about tetanus. (2023, December 4). European Centre for Disease Prevention and Control.
2. Chapeton-Montes, Diana, et al. “The population structure of Clostridium tetani deduced from its pan-genome.” Scientific Reports 9.1 (2019): 11220.
3. Qazi, Omar, et al. “Identification and characterization of the surface-layer protein of Clostridium tetani.” FEMS Microbiology Letters 274.1 (2007): 126–131.
4. Sudarshan, R., Sayo, A. R., Renner, D. R., De Saram, S., Godbole, G., Warrell, C., ... & Coughlan, C. (2025). Tetanus: recognition and management. The Lancet Infectious Diseases.

MSc. Kim Ngoc Son
MSc. Nguyen Duong Ngoc Thoi