ICU Management of Tetanus

Abstract

Tetanus is a major public health concern in low socio economic countries and it carries a high mortality rate. However, the incidence of tetanus in developed nations has greatly reduced due to an excellent vaccine program. Tetanus is caused by a neurotoxin released by Clostridium tetani. C. tetani is a spore-forming bacterium that is widely distributed in soil and it is also found in the intestines and feces of animals such as horses, sheep, cattle, dogs, cats, rats and guinea pigs. The mortality is because of various complications due to muscle spasms, autonomic dysfunction, as well as due to prolonged critical care. Management of tetanus with its complications is in an intensive care unit and the goals of management include stopping further toxin production, neutralization of unbound toxin, management of the airway, control of muscle spasm, treatment of autonomic dysfunction and general supportive management. The effective method of preventing tetanus is by immunization with tetanus toxoid containing vaccines. The vaccine is cheap, effective and safe for all age groups.

1. Introduction

Tetanus is an acute, potentially fatal disease that is characterized by generalized increased rigidity and convulsive spasms of skeletal muscles. It is caused by a neurotoxin released by Clostridium tetani. C. tetani is a spore-forming bacterium that is widely distributed in soil and it is also found in the intestines and feces of animals such as horses, sheep, cattle, dogs, cats, rats and guinea pigs. Agriculturally, soil treated with manure may contain large numbers of spores also. In agricultural areas due to soil treatment with manure, a significant number of human adults may harbor the organism too. It enters the body through breaks in the skin and germinates under anaerobic conditions [1]. Tetanus is a vaccine-preventable disease that remains a common cause of acute critical illness in low-income and middle-income countries (LMICs). It is estimated that the annual mortality of tetanus is around 200,000–300,000 with over a half of these deaths found in neonates. Neonatal tetanus is a severe, often fatal disease caused by a toxin of C. tetani. The World Health Organization defines a confirmed case of neonatal tetanus as an illness in a child who has normal feeding and crying during the first 2 days of life but loses the ability between age 3 and 28 days of life and becomes rigid and has spasms. It occurs through infection of the umbilicus when the cord is cut with an unclean instrument or when substances heavily contaminated with tetanus spores are applied to the umbilical stump. Infants who have not acquired passive immunity from the mother because she has not been immunized are at an increased risk. Tetanus is however relatively rare in the developed world. Where they occur, it is usually in the adult. Neonatal tetanus has been eliminated in Europe [2].

2. Pathophysiology

The C. tetani bacterium is a spore-forming, gram-positive, slender, anaerobic rod. It is heat sensitive and cannot survive in the presence of oxygen. The spores however are extremely resistant to heat and they can survive autoclaving at a temperature up to 121°C for 10–15 min. The spores of C. tetani are widely distributed in the environment and they reside in soil, faeces and dust. Once the spores enter the body through a wound, they germinate in the presence of an anaerobic condition. In some patients, no entry site is seen. Spores of C. tetani can also gain entry into the body through burns, surgery sites or childbirth. It has an incubation period of 2 and 21 days with an average 8 days. The further the injury site is from the central nervous system the longer the incubation period. Shorter incubation periods are associated with severe form of the disease and a higher chance of death. C. tetani produces two exotoxins, tetanolysin and tetanospasmin. Tetanospasmin is a neurotoxin and it is responsible for the clinical presentations of tetanus. This is an extremely potent neurotoxin and it is estimated that the minimum human lethal dose is 2.5 ng/kg of body weight (a nanogram is one billionth of a gram). The toxin spreads into the nervous system by binding to the neuromuscular junction and then being transported backwards into the cell body. Further spread occurs trans-synaptically to adjacent motor and autonomic nerves. The effect of tetanospasmin is by cleaving synaptobrevin which is a vesicle-associated membrane protein which is essential for the release of neurotransmitter. The inhibitory pathways is the most affected there by preventing the release of glycine and g-amino butyric acid (GABA). When interneurones inhibiting alpha motor neurones are affected, there is failure to inhibit motor reflexes [3]. This causes increased muscle tone and rigidity, interposed by sudden and potentially devastating muscle spasms. Muscles of the face are affected early because of their short axonal pathways. Sympathetic neurones become affected later in the disease. Disinhibited autonomic discharge leads to loss of autonomic control, resulting in sympathetic overactivity and increased catecholamine levels. Neuronal binding of the toxin is irreversible. Recovery requires the growth of new nerve terminals, which explains the prolonged duration of the disease.

3. Diagnosis

The diagnosis of tetanus is clinical. History of vaccination, physical examination, signs and symptoms of muscle spasm, rigidity and pain are pointers to presence of tetanus. There are currently no confirmatory laboratory tests. The triad of muscle rigidity, muscle spasms and autonomic instability indicates the presence of the disease.

4. Clinical features

On the basis of clinical findings, four different forms of tetanus have been described.

1. Generalised tetanus

2. Localised tetanus

3. Cephalic tetanus

4. Neonatal tetanus

4.1 Generalised tetanus

Generalized tetanus is the most common form of tetanus accounting for up to 80% of reported cases. It attacks muscles throughout the entire body. Generalized tetanus attacks and inhibits mostly the motor neurons of the CNS and later the neurons of the ANS as well thereby presenting with a descending pattern with uncontrollable muscle contraction affecting muscles of the face and jaw (trismus or locked jaw) being the first sign followed by stiffness of the neck, difficulty in swallowing, and rigidity of abdominal muscles. Other symptoms include elevated temperature, sweating, elevated blood pressure, and episodic rapid heart rate. Spasms may occur frequently and can last for several minutes. Spasms continue for 3–4 weeks. Complete recovery may take months.

4.2 Localised tetanus

Localized tetanus is an uncommon form of the disease in which patients have persistent contraction of muscles in the same anatomic area as the injury. It is most commonly confined to the extremities. These contractions may persist for many weeks before gradually subsiding. Localized tetanus may precede the onset of generalized tetanus but is generally milder.

4.3 Cephalic tetanus

Cephalic tetanus is rare, and results from head injuries or otitis media in which C. tetani is present in the flora of the middle ear or following injuries to the head. There is involvement of the cranial nerves, especially in the facial area and patients may present with facial nerve palsies. The infection may become generalized.

4.4 Neonatal tetanus

Neonatal tetanus is a form of generalized tetanus that occurs in newborn infants born without protective passive immunity because the mother is not immune. It results in high mortality in developing countries and is responsible for up to 50% of death due to tetanus. The infection usually arises from contamination of the umbilical cord during unsanitary delivery practices, absent maternal vaccination and unhygienic cultural practices such as the application of cow dung to the umbilical stump during the neonatal period. In neonatal tetanus, symptoms usually appear from 4 to 14 days after birth, averaging about 7 days [4].

Generally, symptoms of tetanus can be summarized to include neck stiffness, sore throat, dysphagia and trismus. Muscle spasms are extremely painful and can cause tendon to rupture, joint dislocation and bone fractures. Spasm that extends to the facial muscles causes the typical facial expression known as risus sardonicus. Truncal spasm causes opisthotonus. Severe hypoventilation and life-threatening apnoea may occur during prolonged spasms. Hypertension and tachycardia occur mainly from increased sympathetic tone. Autonomic storms are associated with raised catecholamine levels. These alternate with episodes of sudden hypotension, bradycardia and asystole. Other features of autonomic disturbance include salivation, sweating, increased bronchial secretions, hyperpyrexia, gastric stasis and ileus [5].

5. Complications of tetanus

The complications of tetanus result from muscle spasm, autonomic dysfunction, and prolonged critical illness. All systems of the body are involved.

5.1 Respiratory system

Life threatening complications from involvement of the respiratory system include but not limited to apnoea, hypoxia, respiratory failure, laryngeal spasm, atelectasis, aspiration pneumonitis, etc. Prolonged ventilation may lead to ventilator associated pneumonia (VAP) and complications from tracheostomy e.g. tracheal stenosis. Breathing problems occur from tightening of vocal cords and muscle rigidity.

5.2 Cardiovascular system

The cardiovascular complications are from autonomic dysfunction and are the most serious complications. These include tachycardia, hypertension, ischaemia, hypotension, bradycardia, tachyarrhythmias, bradyarrhythmias, Asystole, heart failure. The pathogenesis is said to be due excessively high levels of circulating catecholamines.

Other complication related to the renal and gastrointestinal systems include; high output renal failure, Oliguric renal failure from rhabdomyolysis, urinary stasis, urinary tract infection, gastric stasis, ileus, diarrhoea, haemorrhage. Thromboembolism and skin breakdown has been reported. Dislocation of the temporomandibular and shoulder joints have also been reported. Sepsis with multiple organ failures can also occur with the progression of the disease.

6. Severity grading/prognosis

The Ablett classification of severity is the most commonly used grading system. It grades tetanus infection from mild (Grade I) to very severe (Grade IV) [6]. Prognosis is assessed using the Phillips score and the Dakar score. Both these scoring systems are relatively straightforward schemes which take into account the incubation period and the period of onset as well as presence of neurological and cardiac manifestations. The Phillips score also factors in the state of immune protection (Tables 1–4).

Grade	Characteristics
Grade 1 (mild)	Mild trismus, general spasticity, no respiratory compromise, no spasms, no dysphagia
Grade 2 (moderate)	Moderate trismus, rigidity, short spasms, mild dysphagia, moderate respiratory involvement, ventilatory frequency >30
Grade 3 (severe)	Severe trismus, generalized rigidity, prolonged spasms, severe dysphagia, apnoeic spells, pulse >120, ventilatory frequency >40
Grade 4 (very severe)	Grade 3 with severe autonomic instability involving the cardiovascular system Severe hypertension and tachycardia, alternating with relative hypotension and bradycardia, either of which may be persistent

Table 1.

Ablett classification of severity.

Prognostic factor	Score 1	Score 0
Incubation period	<7 days	>7 days or unknown
Period of onset	<2 days	>2 days
Entry site	Umbilicus, burn, uterine, open fracture, surgical wound, intramuscular injection	All others plus unknown
Spasms	Present	absent
Fever	>38.4°C	<38.4°C
Tachycardia	Neonate > 150 beats/min; Adult > 120 beats/min	Neonate < 150 beats/min; Adult < 120 beats/min
Total score

Table 2.

Prognostic scoring systems in tetanus: Dakar score.

Score	Severity	Mortality
0–1	Mild	˂10%
2–3	Moderate	10–20%
4	Severe	20–40%
5–6	Very severe	˃50

Table 3.

Total score, severity and disease prognosis.

Incubation time:
<48 h
2–5 days	4
5–10 days	3
10–14 days	2
>14 days	1
Site of infection:
Internal and umbilical	5
Head, neck, and body wall	4
Peripheral proximal	3
Peripheral distal	2
Unknown	1
State of protection:
None 10	10
Possibly some or maternal immunisation in neonatal patients	8
Protected > 10 years ago	4
Protected < 10 years ago	2
Complete protection	0
Complicating factors:
Injury or life threatening illness 10	10
Severe injury or illness not immediately life threathening	8
Injury or non-life threatening illness 4	4
Minor injury or illness 2	2
ASA grade 1	0
Total

Table 4.

Prognostic scoring systems in tetanus: Phillips score

Mild <9, moderate 9–16, severe >16.

7. Management

There is currently no treatment for tetanus. Management of the disease requires an emergency and long term supportive care. Three strategic principles apply however apply.

• Neutralization of the toxin that is already in the body

• Destroying the organisms in the body to prevent further toxin release

• Minimizing the effects of the toxin already in the body

7.1 Neutralizing toxin already in the body

Intravenous human tetanus immunoglobulin (HTIG) 150 units/kg intramuscularly is used to neutralize free circulating toxin before it binds to neuronal cell membrane. The HTIG is an effective therapy and it is given as soon as the diagnosis of tetanus is considered. There is available an intravenous preparation of 5000–10,000 IU. HTIG is a specific solvent-detergent-treated plasma derived product obtained from donors immunized with tetanus toxoids. An initial skin sensitivity testing using a dose of 3000–6000 units intramuscularly is given. This drug does not neutralize intracellular toxin which is already fixed to the nerve terminals. HTIG is contraindicated in patients with history of anaphylactic reaction to the active substance or to any of the component of the product. Also patients with deficiency of mmunoglobulin A and the intramuscular test dose is contraindicated in those with severe thrombocytopenia or any coagulation disorder.

7.1.1 Airway management

Respiratory failure has been identified as the commonest direct cause of death from tetanus in the less developed world. This may not be unconnected with lack of ventilator support where it is needed. The Intensivist should anticipate patients at risk of hypoxia and airways obstruction, aspiration hypoventilation, pneumonia, and respiratory arrest. Such patients should be closely monitored and connected to ventilator support as soon as possible. Early airways protection initially with endotracheal tube or tracheostomy is often needed. Ventilator modes used depends on complexity of the ventilators available in the intensive care unit. In the early stages of the disease when rigidity and spasm are prominent, sedation, analgesia and muscular paralysis are required to allow for controlled mandatory ventilation. This mode usually provides rest to the already fatigue muscles of respiration. It is important to note that the controlled mandatory ventilation mode is used only when necessary. Poor lung compliance and oxygenation due to muscular rigidity or pulmonary complications may be overcome by a combination of pressure controlled ventilation and positive end expiratory pressure (PEEP). In the later stages of the disease, modes of ventilation that allow spontaneous ventilation (synchronised intermittent mandatory, continuous positive airway pressure and biphasic positive airway pressure ventilation) are generally preferred and may optimize the respiratory pattern, reduce sedation requirements, minimise muscle wastage, and reduce the likelihood of acquired critical illness neuropathy or myopathy. Mechanical ventilation is better and more comforting for the patient if a tracheostomy is given early. Tracheostomy increases patients comfort, reduced dead space and airway resistance with reduced risk of airway trauma especially in patients convulsing. Endotracheal intubation has been associated with more complications such as subglottic stenosis, vocal cord immobility, laryngeal granuloma, need for deeper sedation when compared to tracheostomy and higher mortality rate. Sedation is an essential component of the management of tetanus patients being ventilated in ICU. It is required to relieve the discomfort and anxiety caused by airway manipulation, ventilation, suction and physiotherapy. Sedation can also minimize agitation yet maximize rest and appropriate sleep. Analgesia is an almost universal requirement for ventilated patients. Combination of opioids and benzodiazepines used for controlling seizures in tetanus gives a good outcome. Adequate sedation and analgesia ameliorates the stress response to tracheal intubation and mechanical ventilation.

7.2 Destroy the organisms in the body to prevent further toxin release

Metronidazole is used to destroy the organisms in the body. It diffuses into the organism and inhibits its protein synthesis by interacting with DNA and causes loss of helical DNA structure. A dose of 30–40 mg/kg/day in three divided doses for children and 0.5 g three times daily for up to 10 days is recommended. Other drugs that are effective include Penicillin G (100,000–200,000 IU/kg/day intravenously, given in four divided doses). Macrolides such as erythromycin given as 30–50 mg/kg/day in three divided doses for children and 0.5 g/kg/day in three divided doses for adults has shown effectiveness. Tetracyclines, clindamycin, cephalosporins and chloramphenicol are also effective. To reduce further bacterial load and toxin, if a wound responsible for tetanus is clear, thorough cleaning of infected site with extensive surgical debridement is recommended if patient is stable. Surgical debridement helps to eradicate spores and necrotic tissues which could lead to conditions ideal for germination. To reduce the risk of releasing tetanospasmin into the bloog stream, it is advised that wound manipulation should be delayed until hours after administration of antitoxin.

7.3 Minimise the effects of the toxin already in the body

Circulating tetanus toxins cause muscle rigidity, spasm and autonomic instability. Treatment of rigidity and spasm is very effective in preventing exhaustion, respiratory failure, aspiration pneumonitis and dysphagia. Spasm and rigidity can be treated effectively with sedation and limiting unnecessary stimulation. Benzodiazepine along or in combination with other drugs such as anticonvulsants have been used with great successes. The first line of treatment is the benzodiazepines.

Diazepam one of the derivative of benzodiazepines and is very effective in tetanus management. It acts by increasing GABA agonism through resistance to endogenous inhibitors of the GABAA receptor. The benefits of diazepam are as anti-convulsant and muscle relaxant that acts to control rigidity and muscle spasms. In addition, diazepam has sedative and anxiolytic effects. Large doses up to 100 mg/h can be administered and may cause mild respiratory depression.

Midazolam, also a benzodiazepine can be used in the absence of Diazepam. It is however relatively short-acting. Morphine can be equally efficacious and is usually used as an adjunct to benzodiazepine sedation.

Propofol has also been used successfully with rapid recovery occurring once the infusion is stopped however, in order to achieve adequate plasma concentrations to relieve muscle rigidity, mechanical ventilation is necessary.

In a patient with tetanus on mechanical ventilation, neuromuscular blocking agents can be used to control the muscle spasm if it continues despite the use of sedatives. Vecuronium is a short-acting neuromuscular blocker. It has minimal cardiovascular effects and does not release histamines. The use of pancuronium and atracurium is not recommended because pancuronium causes tachycardia while atracurium causes bradycardia and hypotension which may trigger mortality in the patient with tetanus. Newer agents such as pipercuronium and rocuronium are long acting and provide good haemodynamic stability they are however expensive compared with older drugs.

Anticonvulsants such as phenobarbitone, (which enhances GABA activity) and phenothiazine such as and chlorpromazine may be used to provide additional sedation. When sedation alone is inadequate, neuromuscular blocking agents and intermittent positive pressure ventilation may be required, usually for a prolonged period.

Baclofen is a structural analogue of GABA_B receptor agonist that inhibits pre-synaptic acetylcholine release and synaptic medullar reflexes. These effects help in an anti-spastic action. They act by lowering calcium permeability in primary afferents. Intrathecal administration of 500-2000μg daily of baclofen had caused decrease muscle spasm in generalised tetanus [7].

7.4 Autonomic instability

Circulatory collapse is a major cause of mortality in tetanus and this is caused by autonomic instability. Sudden cardiac arrest is common and is thought to be precipitated by a combination of high catecholamine levels and the direct action of the tetanus toxin on the myocardium. Prolonged sympathetic activity may end with profound hypotension and bradycardia. Parasympathetic over activity may lead to sinus arrest. Direct damage to the vagal nucleus by the tetanus toxin has been implicated. Sedation with Benzodiazepines, anticonvulsant medication and morphine is the first line maneuver to control autonomic instability and also magnesium sulphate has been used as a preventive measure with success.

Magnesium sulfate is a pre-synaptic neuromuscular blocker. It inhibits catecholamine release from nerves and adrenal medulla and also reduces receptor responsiveness to released catecholamines, anticonvulsants, and vasodilators. Magnesium sulphate is a calcium antagonist in the myocardium and neuromuscular junction and inhibits the release of parathyroid hormone thereby decreasing calcium levels. Doses are initiated with loading dose 75–80 mg/kg in 30 min and followed by 2 g/h in patients under 60 years and 1 g/h for patients over 60 years. Morphine is very useful in maintaining cardiovascular stability. The mechanism of action of morphine includes replacement of endogenous opioids, reduction of sympathetic reflex activity and histamine release [8]. Phenothiazine especially chlorpromazine which acts as anticholinergic and α adrenergic antagonism also play a role in maintaining cardiovascular stability and used as a sedative.

B-blockade, although theoretically useful to control episodes of hypertension and tachycardia, is associated with sudden cardiovascular collapse, pulmonary oedema and death.

7.5 Supportive care

Patients with tetanus suffer weight loss due to several factors. These include inability to swallow, autonomic induced alterations in gastrointestinal function, increased metabolic rate due to pyrexia and muscular activity from convulsion and seizure. Nutrition should therefore be established as early as possible. Due to trismus, oral feeding is not possible. Nasogastric tube should be passed as early as possible to commence feeding. High caloric nutritional supplement is required to meet the high metabolic demand of tetanus. Parenteral nutrition is preferred but it is expensive and majority of tetanus patients are from a poor socio-economic status.

Nosocomial infection such as VAP is common among critically ill patients that are ventilated. The prevalence of VAP is a common indicator for safety and quality of care in critically ill patients admitted to the ICU. This is associated with increased mortality among ventilated patients. Measures taken to prevent VAP include strict hand hygiene with alcohol solutions before airway management, continuous aspiration of subglottic secretions, oral hygiene with chlorhexidine, semi recumbent positioning of patients where possible and selective decontamination of the digestive tract or selective oropharyngeal decontamination.

Venous thromboembolism (VTE) is a common and major complication in the critically ill patients. The use of intermittent pneumatic compression or graduated compression stockings with regular turning of patient help to prevent thromboembolism.

Other supportive measures foot drop splint to prevent ankle contracture, limb and chest physiotherapy, regular turning of patient or use of air/water mattress to prevent decubitus ulcer, care of the patient should be in dark room with minimal stimulus and psychosocial support.

8. Prevention

The effective method of preventing tetanus is by immunization with tetanus toxoid containing vaccines. The vaccine is cheap, effective and safe for all age groups. In children, three doses are given from as early as six weeks of life and repeated at intervals of 4 weeks. It is also advised that three booster doses are given to confer lifelong immunity. It is also administered to pregnant women during pregnancy as a part of ante natal care package and also women in the reproductive age groups. To maintain high level of protection, individuals with cuts and open wound are given the tetanus toxoid containing vaccine [9].

9. Conclusion

Tetanus is a vaccine preventable disease but it has remained a public health problem in developing countries mostly due to poor vaccine coverage, poverty and low levels of education. All wounds other than clean minor ones should be considered tetanus prone therefore, HTIG should be considered. The diagnosis of tetanus is clinical and it can be fatal if missed. The mortality rate of tetanus is high and prolonged ICU care may be required. The outcome depends on early diagnosis, identification and management of complications and a good supportive care which the patient receives.