Department of Anaesthesia and Intensive Care, Royal United Hospital, Combe Park, Bath BA1 3NG, UK 1Present address: Intensive Care Unit, Royal Adelaide Hospital, Adelaide, South Australia*Corresponding author
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Abstract |
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Br J Anaesth 2001; 87: 47787
Keywords: infection, tetanus; complications, autonomic dysfunction; intensive care, management; complications, death
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Introduction |
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Epidemiology |
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Microbiology |
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Vaccination |
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In the USA, more than 70% of cases78 and 80% of deaths45 occur in those over 50 yr. Similar proportions are reported in Europe.89 In the UK and USA, serological surveys have demonstrated an increasing proportion of patients with inadequate immunity as age increases: 4966% of patients over 60 yr had antibody levels below the protective level22 45 91 97 115 Some have never been vaccinated, while others have lost their immunity.89
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Pathophysiology |
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Tetanospasmin leads to the clinical syndrome of tetanus. This toxin may constitute more than 5% of the weight of the organism.74 It is a two-chain polypeptide of 150 000 Da which is initially inactive. The heavy chain (100 000 Da) and the light chain (50 000 Da) are linked by a protease sensitive loop that is cleaved by tissue proteases leaving a disulphide bridge linking the two chains. The carboxyl terminus of the heavy chain binds to neural membrane and the amino terminus facilitates cell entry.120 The light chain acts pre-synaptically to prevent neurotransmitter release from affected neurones. Released tetanospasmin spreads to underlying tissue and binds to gangliosides GD1b and GT1b on the membranes of local nerve terminals. If toxin load is high, some may enter the bloodstream from where it diffuses to bind to nerve terminals throughout the body. The toxin is then internalized and transported intra-axonally and retrogradely39 to the cell body.65 Transport occurs first in motor9 and later in sensory and autonomic nerves (Fig. 2).116 Once in the cell body the toxin can diffuse out so affecting and entering nearby neurones. When spinal inhibitory interneurones are affected symptoms occur.11 Further retrograde intraneural transport occurs with toxin spreading to the brainstem and midbrain. This passage includes retrograde transfer across synaptic clefts by a mechanism that is unclear.
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Uncontrolled disinhibited efferent discharge from motor neurones in the cord and brainstem leads to intense muscular rigidity and spasm, which may mimic convulsions. The reflex inhibition of antagonist muscle groups is lost and agonist and antagonist muscles contract simultaneously. Muscle spasms are intensely painful and may lead to fractures and tendon rupture. Muscles of the jaw, face, and head are often involved first because of their shorter axonal pathways. The trunk and limbs follow but peripheral muscles in the hands and feet are relatively spared.
Disinhibited autonomic discharge leads to disturbances in autonomic control, with sympathetic overactivity and excessive plasma catecholamine levels.
Neuronal binding of toxin is thought to be irreversible. Recovery requires the growth of new nerve terminals11 33 98 which explains the prolonged duration of tetanus.
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Clinical features |
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There is a clinical triad of rigidity, muscle spasms and, if severe, autonomic dysfunction. Neck stiffness, sore throat, and difficulty opening the mouth are often early symptoms.4 37 Masseter spasm causes trismus or lockjaw. Spasm progressively extends to the facial muscles causing the typical facial expression, risus sardonicus, and muscles of swallowing causing dysphagia (Fig. 3). Rigidity of the neck muscles leads to retraction of the head. Truncal rigidity may lead to opisthotonus and respiratory difficulty with decreased chest wall compliance.
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In the commonest form of tetanus, generalized tetanus, muscles throughout the body are affected. The muscles of the head and neck are usually affected first with progressive caudal spread of rigidity and spasm to affect the whole body. The differential diagnosis includes orofacial infection, dystonic drug reactions, hypocalcaemia, strychnine poisoning, and hysteria.
With lower toxin loads and peripheral injuries local tetanus is seen. Spasm and rigidity are restricted to a limited area of the body.35 Mortality is greatly reduced. An exception to this is cephalic tetanus when localized tetanus from a head wound affects the cranial nerves; paralysis rather than spasm predominates at presentation (Fig. 4), but progression to generalized tetanus is common and mortality is high.57
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In addition to the cardiovascular system, other autonomic effects include profuse salivation and increased bronchial secretions. Gastric stasis, ileus, diarrhoea, and high output renal failure may all be related to autonomic disturbance.
The involvement of the sympathetic nervous system is established.64 The role of the parasympathetic system is less clear. Tetanus has been reported to induce lesions in the vagal nuclei,8 while locally applied toxin may lead to excessive vagal activity.5 Hypotension, bradycardia, and asystole may arise from increased vagal tone and activity.37 111
Natural history
The incubation period (time from injury to first symptom) averages 710 days, with a range of 160 days. The onset time (time from first symptom to first spasm) varies between 17 days. Shorter incubation and onset times are associated with more severe disease. The first week of the illness is characterized by muscle rigidity and spasms, which increase in severity. Autonomic disturbance usually starts several days after the spasms and persists for 12 weeks. Spasms reduce after 23 weeks, but stiffness may persist considerably longer. Recovery from the illness occurs because of re-growth of axon terminals11 33 98 and by toxin destruction.25
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Severity grading |
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Altered cardiovascular physiology |
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Severe uncomplicated tetanus was marked by a hyperkinetic circulation. Tachycardia was universal with hypertension, raised stroke volume index, and raised cardiac index. Other findings were low normal systemic vascular resistance and normal left- and right-sided filling pressures. These findings were similar to those of James and Manson.58 The hyperkinetic state was exaggerated during poor relaxation and increased spasm activity. The haemodynamic abnormalities became less marked during periods of full muscular relaxation but measurements only gradually returned to normal ranges during recovery from the disease. A fluid challenge of 2000 ml increased left heart filling pressures and cardiac index but these effects were very transient. During autonomic storms with marked cardiovascular instability, patients fluctuated from a hyperstimulated state of hypertension (arterial pressure up to 220/120 mm Hg) and tachycardia (heart rate 130190 beats min1) to one of profound depression with hypotension (as low as 70/30 mm Hg), bradycardia (5090 beats min1) and a fall in CVP (reducing from 6 to 1 cm H2O). Invasive monitoring showed these changes to be a result of a rapid, marked alteration in systemic vascular resistance index (SVRI), falling from 2300 to less than 1000 dynes s cm5 m2. There was little change in cardiac index or filling pressures. Patients with grade IV disease were less likely than those with less severe disease to raise cardiac index or cardiac work indices in response to fluid load or during alterations in vascular resistance seen during autonomic storms. One patient with severe sustained hypertension was found to have massively raised vascular resistance with SVRI greater than 4500 dynes s cm5 m2. In complicated tetanus, measurements varied widely with no consistent findings.
The hyperkinetic circulation is largely because of increased basal sympathetic activity and muscle activity, with a lesser effect from raised core temperature. The low-normal SVRI is because of extensive vasodilation in metabolically active muscles. As oxygen extraction ratio does not alter in tetanus, the increased demand must be delivered by increased blood flow. Poor spasm control exaggerates these effects. Fluid loading causes only a transient rise in filling pressures, cardiac index, and LVSWI, because the circulation is widely vasodilated and hence is a high capacitance system in comparison to normal controls. In uncomplicated tetanus, the cardiovascular system, therefore, mimics that of the normal patient undergoing intense exercise. Grade IV patients appear less able to increase cardiac performance and, therefore, are more susceptible to profound hypotension and shock during acute vasodilatory storms. The mechanism is unclear but may relate to sudden withdrawal of catecholamine stimulation or a direct action of tetanus toxin on the myocardium. Altered myocardial function may be because of persistently raised catecholamine levels95 but abnormal function may occur even in the absence of sepsis or high catecholamine levels.54
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Altered respiratory physiology |
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Altered renal physiology |
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Management |
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Neutralization of unbound toxin
Human tetanus immune globulin 36000 units is given i.m.2 4 48
Removal of the source of infection
Where present, obvious wounds should be surgically debrided.2 37 48 Penicillin has been widely used for many years but is a GABA antagonist and associated with convulsions.61 Metronidazole is probably the antibiotic of choice. It is safe and comparative studies with penicillin suggest at least as good results.3 121 Erythromycin, tetracycline, chloramphenicol, and clindamycin are all accepted as alternatives.2 4 37 48
Control of rigidity and spasms
Avoidance of unnecessary stimulation is mandatory, but the mainstay of treatment is sedation with a benzodiazepine. Benzodiazepines augment GABA agonism, by inhibiting an endogenous inhibitor at the GABAA receptor. Diazepam may be given by various routes, is cheap and widely used, but long acting metabolites (oxazepam and desmethyldiazepam) may lead to cumulation and prolonged coma. Doses as high as 100 mg h1 have been reported.72 Midazolam has been used with less apparent cumulation.50 Additional sedation may be provided by anticonvulsants, particularly phenobarbitone (which further enhances GABAergic activity)60 and phenothiazines, usually chlorpromazine.25 Propofol has been used for sedation with rapid recovery on stopping the infusion.13 83
When sedation alone is inadequate, neuromuscular blocking agents and intermittent positive pressure ventilation may be required for a prolonged period. Traditionally, the long acting agent pancuronium has been used.36 However, pancuronium inhibits catecholamine re-uptake and could worsen autonomic instability in severe cases. There have been isolated reports of worsening hypertension and tachycardia associated with its use.18 40 But Dance reported no difference in complications in those treated with pancuronium compared with other neuromuscular blocking drugs.25 Vecuronium is free from cardiovascular side-effects and histamine release but is relatively short-acting.40 88 The use of an atracurium infusion in tetanus for 71 days has been reported.81 In this patient, with normal renal and hepatic function, there was no cumulation of laudanosine, the epileptogenic metabolite of atracurium. Longer-acting agents are preferable as they lend themselves to administration by intermittent bolus rather than requiring infusion. Prolonged use of aminosteroid neuromuscular blocking agents (vecuronium, pancuronium, rocuronium, and pancuronium), particularly by infusion, has been associated with critical illness neuropathy and myopathy,41 but this has not been reported in tetanus. Of the newer agents, pipecuronium and rocuronium are long acting clean agents but are expensive. Individual drugs have not been compared in randomized trials.
The use of dantrolene to control refractory spasms has been reported in one case.107 Neuromuscular blocking drugs were unnecessary after its administration, paroxysmal spasms stopped and the patients condition improved.
Sedation with propofol has allowed control of spasms and rigidity without the use of neuromuscular blocking drugs.13 Examination of the EMG and neuromuscular function during propofol boluses.12 showed an 80% reduction in EMG activity without alteration of function at the neuromuscular junction. However, drug levels were closer to anaesthetic than sedative concentrations and mechanical ventilation would be required.
Intrathecal baclofen (a GABAB agonist) has been reported in several small series with varying success.32 92 99 Doses ranged from 500 to 2000 µg each day, given as boluses or infusion. Larger doses and boluses were associated with more side-effects.32 In all the reports, a significant number of patients developed coma and respiratory depression necessitating ventilation.32 99 In some cases, adverse effects were reversible with the GABAA antagonist flumazenil, but this is not reliable.32 The technique is invasive, costly and facilities for artificial ventilation must be immediately available.
Control of autonomic dysfunction
Many different approaches to the treatment of autonomic dysfunction have been reported. Most are presented as case reports or small series. There is a lack of comparative or controlled studies. In general, outcome measures have been limited to haemodynamic data rather than survival or morbidity. Non-pharmacological methods of preventing autonomic instability rely on fluid loading of up to 8 litres day1.66 120
Sedation is often the first treatment. Benzodiazepines, anticonvulsants, and particularly morphine are frequently used. Morphine is particularly beneficial as cardiovascular stability may occur without cardiac compromise.18 93 94 Dosages vary between 20 and 180 mg day1. Proposed mechanisms of action include replacement of endogenous opioids,11 reduction in reflex sympathetic activity and release of histamine.85 Phenothiazines, particularly chlorpromazine are also useful sedatives; anticholinergic and -adrenergic antagonism may contribute to cardiovasular stability.58 90
Initially ß-adrenergic blocking agents, such as propranolol, were used to control episodes of hypertension and tachycardia,37 64 90 but profound hypotension, severe pulmonary oedema and sudden death were all found to occur.17 37 58 Labetolol, which has combined - and ß-adrenergic blocking effects has been used, but no advantage over propranolol was demonstrated (possibly because its
activity is much less than its ß activity31 34) and mortality remained high.117 In recent years, the short-acting agent, esmolol, has been used successfully.68 Although good cardiovascular stability was achieved, arterial catecholamine concentrations remained elevated.
Sudden cardiac death is a feature of severe tetanus. The cause remains unclear but plausible explanations include sudden loss of sympathetic drive, catecholamine-induced cardiac damage and increased parasympathetic tone or storms. Persisting beta block could exacerbate these causes because of negative inotropism or unopposed vasoconstrictor activity, leading to acute cardiac failure, particularly as sympathetic crises are associated with high systemic vascular resistance and normal or low cardiac output. Isolated use of ß-adrenergic block with long acting agents, therefore, cannot be recommended.
Postganglionic and -adrenergic blocking agents such as bethanidine, guanethidine, and phentolamine have been successfully used with propranolol,62 90 along with other similar agents such as trimetaphan, phenoxybenzamine, and reserpine.87 A disadvantage of this group of drugs is that induced hypotension may be difficult to reverse, tachyphylaxis occurs and withdrawal can lead to rebound hypertension.
The successful management of autonomic disturbance with i.v. atropine has been reported.30 Doses of up to 100 mg h1 were used in four patients. The author argues that tetanus is a disease of acetylcholine excess. He suggests these extremely high doses achieve not only muscarinic but also nicotinic block providing autonomic block, central sedation, and even neuromuscular block. Block of the parasympathetic nervous system was reported to markedly reduce secretions and sweating.
The 2-adrenergic agonist clonidine has been used orally or parenterally, with variable success. Acting centrally, it reduces sympathetic outflow, thus, reducing arterial pressure, heart rate, and catecholamine release from the adrenal medulla.16 Peripherally, it inhibits the release of norepinephrine from pre-junctional nerve endings. Other useful effects include marked sedation and anxiolysis. Two case reports reported opposing results, one with good control105 and one with no alteration in haemodynamic instability.15 Gregorakos used i.v. clonidine 2 µg kg1 tds in 17 of 27 patients treated over 12 yr.46 The group randomized to receive clonidine had a significantly lower mortality than those receiving conventional treatment.
Epidural49 104 and spinal bupivacaine102 have been reported to reduce cardiovascular instability. However, catecholamine infusions were required to maintain adequate arterial pressure.
Magnesium sulphate has been used both in artificially ventilated patients to reduce autonomic disturbance58 72 and in non-ventilated patients to control spasms.6 Magnesium is a pre-synaptic neuromuscular blocker,79 blocks catecholamine release from nerves and adrenal medulla,114 reduces receptor responsiveness to released catecholamines,79 is an anticonvulsant119 and a vasodilator.53 It antagonises calcium in the myocardium and at the neuromuscular junction and inhibits parathyroid hormone release so lowering serum calcium. In overdose, it causes weakness and paralysis,77 with central sedation10 82 although the latter is controversial.58 Hypotension and bradyarrhythmia may occur.73 It is, therefore, mandatory to maintain levels in the therapeutic range. In the report by James and Manson, patients with very severe tetanus were studied and magnesium was found to be inadequate alone as a sedative and relaxant, but an effective adjunct in controlling autonomic disturbance. Serum concentrations were difficult to predict and regular monitoring of serum magnesium and calcium levels were required.58 Muscular weakness was apparent and ventilation was required in all cases. Attygalle and Rodrigo6 studied patients at an earlier stage of the illness yet all cases were probably severe and had undergone tracheostomy. They used similar doses of magnesium to try to avoid sedatives and positive pressure ventilation. They reported successful control of spasms and rigidity. Magnesium concentrations were predictable and readily kept within the therapeutic range, by using the clinical sign of the presence of a patella tendon reflex. In both studies, the absence of hypotension and bradycardia was in contrast to the results with beta block. Both authors agreed that tidal volume and cough may be impaired and secretions increased. Ventilatory support must be immediately available.7 59 More work is necessary on the role of magnesium both with regard to its physiological effect on neuromuscular function in the presence of tetanus and to establish what role, if any, it has in the routine management of severe tetanus.
Several drugs show potential for use in the future. Sodium valproate blocks GABA-aminotransferase, thereby inhibiting GABA catabolism. In animal studies, this prevents the clinical effects of tetanus toxin.42 Angiotensin converting enzyme inhibitors may also help by inhibiting the synthesis of angiotensin II, which increases norepinephrine synthesis and release from the nerve endings.120 Dexmedetomidine, a more potent 2-adrenergic agonist than clonidine, may also have an effect in reducing sympathetic overactivity.87 Finally, adenosine, which reduces presynaptic norepinephrine release and antagonizes the inotropic effects of catecholamines, has theoretical potential.87 To date, its clinical use in this setting has not been discussed.
Supportive intensive care treatment
Weight loss is universal in tetanus.37 Contributory factors include inability to swallow, autonomic induced alterations in gastrointestinal function, increased metabolic rate from pyrexia and muscular activity and prolonged critical illness. Nutrition should, therefore, be established as early as possible. Enteral nutrition is associated with a lower incidence of complications and is cheaper than parenteral nutrition. Percutaneous gastrostomy may avoid the complications associated with nasogastric tube feeding52 and is easily performed on the intensive care unit under sedation.
Infective complications of prolonged critical illness including ventilator-associated pneumonia are common in tetanus.46 112 Securing the airway early in the disease and preventing aspiration and sepsis are logical steps in minimizing this risk. As artificial ventilation is often necessary for several weeks37 tracheostomy is usually performed after intubation. The percutaneous dilatational method20 47 appears particularly suitable for patients with tetanus.29 70 This straightforward bedside procedure avoids transfer to and from the operating theatre with the attendant risk of provoking autonomic instability. Prevention of respiratory complications also involves meticulous mouth care, chest physiotherapy, and regular tracheal suction, particularly as salivation and bronchial secretions are greatly increased. Adequate sedation is mandatory before such interventions in patients at risk of uncontrolled spasms or autonomic disturbance and the balance between physiotherapy and sedation may be difficult to achieve.
Other important measures in the routine management of patients with tetanus, as with any long-term critical illness, include prophylaxis of thromboembolism, gastro-intestinal haemorrhage, and pressure sores. The importance of psychological support should not be underestimated.
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Complications |
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Mortality and outcome |
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Severe cases of tetanus generally require ICU admission for approximately 35 weeks.26 37 58 72 92 109 111 Recovery can be expected to be complete, with return to normal function. However, in one of the few follow-up studies in survivors of tetanus, persisting physical and psychological problems were frequent.55
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Conclusions |
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References |
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