Tetanus and Botulism: Intensive Care Management

61 Tetanus and Botulism: Intensive Care Management

Demócrito de Barros Miranda Filho ¹, Ricardo Arraes de Alencar Ximenes ²

¹ Professor Associado de Doenças Infecciosas e Parasitárias da Faculdade de Ciências Médicas, Universidade de Pernambuco. Chefe do Núcleo de Epidemiologia e Infectologista da Comissão de Controle de Infecção Hospitalar do Hospital Barão de Lucena. Doutor em Doenças Infecciosas e Parasitárias pela Universidade de São Paulo

² Professor Associado do Departamento de Medicina Tropical da Universidade Federal de Pernambuco. Professor Associado do Departamento de Medicina Clínica da Faculdade de Ciências Médicas, Universidade de Pernambuco. Doutor em Epidemiologia pela London School of Hygiene and Tropical Medicine, University of London

61.1 Introduction

Tetanus and botulism are infectious, non-contagious diseases caused by neurotoxins produced by anaerobic bacteria Clostridium tetani and Clostridium botulinum. These neurotoxins are highly neurotropic and are among the most violent and powerful toxins known. Tetanus is characterized by spastic paralysis due to blockage of inhibitory circuits in the spinal cord, while botulism is characterized by flaccid paralysis due to inhibition of the release of acetylcholine at the neuromuscular junction. Both conditions are associated with high mortality and rapid progression to severe forms, and should therefore be treated in intensive care units (ICUs), preferably in reference services.

61.2 Development

Tetanus results from contamination of a wound by Clostridium tetani spores that, under anaerobic conditions, convert to the vegetative form and thus can multiply, producing tetanospasmin. The toxin initially circulates through the bloodstream before migrating over hours or days by motor nerve fibres to the central nervous system (motor neurons of the spinal or cranial nerve nuclei), blocking the inhibitory interneurons of Rushaw and allowing stimulation of the lower motor neurons by impulses coming from the brain and sensory regions. The result is spasticity and muscle spasms. Manifestations of hyperexcitability are due to the action of tetanospasmin which increases acetylcholine release and decreases the levels of glycine.

In botulism the toxin absorbed in the gastrointestinal tract or in a wound spreads via hematogenous route to the nerve endings, more specifically the presynaptic membrane of the neuromuscular junction, blocking the release of acetylcholine, resulting in flaccid paralysis. Botulinum toxin most often it is ingested in food contaminated by Clostridium botulinum, although in special situations, the toxin can be produced after the ingestion of spores that germinate in the faeces or the contaminated wound under anaerobic conditions.

With tetanus the diagnosis is based exclusively on the clinical picture and history of injury and requires a high index of suspicion to identify the early signs and symptoms and disease progression. The diagnosis of botulism is based on the history and clinical picture and specific laboratory tests, although the early recognition of initial clinical manifestations, enabling immediate therapeutic intervention, is critical in the prognosis of the disease, especially when it is the index case of a foodborne outbreak.

Tetanus is characterized by the prolonged contraction and spasms of skeletal muscles. The generalized form of tetanus is the most common. Usually, the first clinical manifestation of tetanus is contracture of the muscles of mastication, which progresses to trismus (lockjaw). Dysphagia may also appear at the initial stage and is characterized by “choking” when the patient tries to swallow. Stiffness of the facial muscles causes accentuation of the natural creases of the face, twitching of the nostrils and lips (sardonic smile), wrinkled forehead, arching eyebrows, and closed eyelids, giving a characteristic expression known as tetanic facies. In this descending pattern of manifestations, the neck muscles are the next involved, with stiff neck, then the paravertebral muscles, the chest and the intercostal muscles, which can make breathing difficult. In this phase the most frequent complaint is neck and back pain. Stiffness may also involve the abdominal muscles and limbs. As the condition progresses, spasms can increase in intensity and duration and may be triggered by various stimuli (light, noise, urination, defecation, accumulation of bronchial secretions, etc.) or arise spontaneously. Paraspinal muscle spasm may cause crushing and fracture of vertebrae. The most serious signs of progress are dysfunctions of the autonomic nervous system: profuse sweating; fluctuations in blood pressure that can be rapidly followed by cardiovascular collapse, instability of the heart; ileus; and fluctuations in blood glucose levels. The patient remains lucid throughout the course of the illness. Fever is uncommon and usually occurs when there is secondary infection in the “gateway” or, more frequently in the respiratory tract. The incubation period (time between injury and appearance of the first symptom) is ≤10 days and the period of progression (time between the first symptom and the first spasm) ≤48 hours, the time elapsed between the occurrence of the first tetanus symptom and admission ≤36 hours and the occurrence of spasms in the first 24 hours of hospitalization are indicators of poor prognosis and may be useful to guide treatment choice. Before intensive care became available, mortality due to tetanus was caused by spasms of the glottis, aspiration and respiratory infection. Since the wider availability of intensive care, complications associated with disruption in the autonomous nervous system have become the leading causes of death. The course of the illness begins to decline 2 to 4 weeks after onset, initially with improved autonomic nervous system function, followed by cessation of spasms, and slow and gradual reduction of muscle contracture. Remission usually occurs within days or weeks.

The hallmark of botulism is descending flaccid paralysis that usually begins in the territory of cranial nerves and manifesting as blurred vision, unilateral or bilateral palpebral ptosis, difficulty converging the eyes, double vision and ophthalmoplegia, weakness of the mastication muscles, swallowing and speech, with consequent dysarthria and dysphasia. Muscle weakness may progress symmetrically to neck muscles, trunk and limbs, causing difficulty sustaining the neck, dyspnea, respiratory failure and flaccid quadriplegia. Autonomic nervous system dysfunction is characterized by dilated pupils and absence of photoreactivity, dry mouth, ileus, fluctuations in blood pressure and heart rate, sweating and urinary retention. As with tetanus, the patient with botulism retains clear senses and mental status during the course of the disease. In foodborne botulism, the most common form in adults, the intoxication results from the ingestion of botulinum toxin and can start with nausea, vomiting, diarrhoea and abdominal pain, with or without concomitant neurological symptoms. In wound botulism, as the toxin is produced and absorbed at the wound site, there is no gastrointestinal symptoms, but fever may occur. Intestinal botulism is more common in children and occurs after the ingestion of Clostridium botulinum that start toxin production. The initial symptoms are constipation and irritability, followed by neurological symptoms. In untreated cases, death can result from airway obstruction or respiratory failure. The disease can progress over 1-2 weeks and stabilize for more than 2 or 3 weeks. The recovery phase can be very slow in severe cases and last for several months.

Although the diagnosis of tetanus is exclusively clinical and epidemiological, with botulism the laboratory may have fundamental importance in confirmation of diagnosis, identify the type of toxin, and in some cases, isolate Clostridium botulinum, although the presence of the bacterium is not conclusive for diagnosis. The detection of toxin in serum or in the content of vomiting, gastric lavage and/or intestinal tract and faeces remains the standard method for diagnosis. Considering that this is a life-threatening intoxication and that early treatment can define therapeutic success, collecting and sending biological material for laboratory examination should be done as soon as possible, preferably within the first 7 days of illness and before the administration of antibotulinic serum. The most widely used diagnostic test is still the mouse bioassay, although a more rapid immunoassay for the detection of botulinum neurotoxin has recently been developed. Electromyography may be useful in identifying the location of involvement, the characteristic lesion being at the neuromuscular junction. Repetitive nerve stimulation shows an increase in the amplitude of the motor potential, and these changes disappear after clinical recovery.

The differential diagnosis for tetanus should include strychnine poisoning; bacterial meningitis; tetany due to hypocalcemia; rabies; hysteria; intoxication from metoclopramide and neuroleptics; inflammation of the mouth and pharynx that can be accompanied by trismus; peritonitis; neck stiffness due to acute cervical osteoarthritis; neck stiffness; septicaemic spondylitis; and seizures.

The differential diagnosis for botulism is with the Guillain-Barré and Müller Fisher syndromes, myasthenia gravis, stroke, central nervous system tumours and alcoholic coma.

Any case of botulism should be reported immediately to health authorities so that measures of investigation and containment of outbreaks can be promptly adopted. Even small outbreaks of foodborne botulism can precipitate a national emergency and overload the ICU.

61.3 Treatment

Because both are potentially life-threatening conditions with an unpredictable evolution, tetanus and botulism should be treated at an ICU, preferably with trained and qualified medical and nursing staff. In Pernambuco, Brazil, the centralization of care in the ICU with an experienced team specializing in the treatment of tetanus has resulted in a significant reduction in mortality.

The treatment of tetanus has the following objectives: neutralization of the toxin, elimination of focus, and symptomatic treatment.

61.3.1 Neutralization of the Toxin

Human anti-tetanus immunoglobulin (HTIG) is given intramuscularly (IM) at a dose of 1000 IU to 3000 IU, although Blake and Feldman (1976), in a retrospective study, found the same efficacy with 500 IU. HTIG should not be administered intravenously (IV). The anti-tetanus serum (ATS) can be used as a second choice at a dose from 10,000 to 20,000 IU IM or IV at any age. The administration of the ATS should be preceded by a skin sensitivity test. If the patient tests negative, promethazine is administered IM 15 minutes before injecting the serum. If the test is positive, ATS cannot be administered and HTIG is given.

A randomized clinical trial conducted by the authors of this chapter compared patients who received HTIG by intrathecal and intramuscular routes with a group treated with HTIG intramuscularly. The group that received HTIG via intrathecal and IM benefited from a better response in relation to various criteria: better clinical outcome; shorter hospitalization time and fewer spasms; lower proportion of overall complications such as respiratory infection and need for artificial ventilation; shorter time on ventilation and lower mortality rate, although for this last variable the difference was not statistically significant. The HTIG was preservative-free, at a dose of 1000 IU, injected into the subarachnoid space by suboccipital or lumbar puncture. In a recent meta-analysis, Kabura et al. (2007) found the intrathecal administration of antitoxin was more beneficial than IM administration for the treatment of tetanus.

61.3.2 Elimination of Focus

The suspicious focus should be widely debrided to remove foreign bodies and necrotic tissue. Prior systemic administration of tetanus antitoxin is recommended. The wound should be cleaned with oxidant liquids such as hydrogen peroxide, potassium permanganate 1: 5000 or aqueous solution of iodine.

Antibiotic treatment can be done with metronidazole at a dose of 1-1.5 g day (15-30 mg/kg/day) divided into 3 parts (8/8 hours) or even a single dose/day for 7-10 days or crystalline G penicillin at a dose of 12-15 million IU/day (200,000 IU/kg/day) in equal fractions of 4/4 hours for 7-10 days. Other alternatives are clindamycin, ampicillin-sulbactam and erythromycin.

61.3.3 Symptomatic Treatment

Among muscle relaxants and sedatives, benzodiazepines, barbiturates and phenothiazines have been used more frequently. The diazepines are considered by most authors as the drug of choice as they have a sedative and relaxant action and are inexpensive. The initial dose is 10 mg IV at intervals ranging from 12/12 hours to 1/1 hour. Attention should be paid to the level of consciousness and respiratory depression, especially among the elderly. Doses should be adjusted according to the patient’s response and severity of the case. The observed side effects are: behaviour disorders, diplopia, dizziness and ataxia. Cases of prolonged coma due to residual effect have been observed in tetanus treated with diazepines, especially among elderly patients. Chlorpromazine also has a sedative and relaxant action and can be combined with diazepines in severe cases (dose of 25 mg IV with a minimum interval of 6 hours). The most frequent side effects include tachycardia, pallor, hypotension, glucosuria, jaundice and sweating.

In cases of serious illness in which muscle spasms do not remit with high-dose muscle relaxants, pancuronium or vecuronium can be used. The use of neuromuscular blocking requires that the patient is mechanically ventilated and sedated. Pancuronium is most widely used because of its low cost and long half-life, at a dose of 0.1 mg/kg, which may be repeated up to 1/1 hour. In cases of severe cardiovascular instability, vecuronium is preferred due to its lack of cardiovascular side effects. Atracurium can also be an alternative, although it is more expensive and can cause cardiovascular instability.

There is no consensus on the most appropriate way to treat autonomic nervous system dysfunctions and most publications are based on case reports or small series. It is expected that an ideal treatment regimen will be effective in stabilizing the cardiovascular system, while preserving compensatory functions to prevent sudden death. In cases of severe, prolonged tachycardia, associated with consistently elevated blood pressure or blood pressure instability, morphine can be used at an initial dose of 5-10 mg 8/8 or even 4/4 hours, SC or IV. In more severe cases, the dose can vary from 240 to 2500 mg/day or 0.01 to 0.1 mg/kg/minute with continuous infusion. However, when very high doses are needed, its use should be limited to short periods of time.

Thwaites et al. (2006), in a randomized and double-blind study testing the effect of magnesium sulphate in an IV solution for the control of spasms and autonomic nervous system dysfunction, observed a reduction in the need for verapamil to control the tachycardia associated with autonomic nervous system dysfunction.

A number of patients with tetanus will require tracheostomy during its clinical course, even though some may not require mechanical ventilation. Tracheostomy should preferably be performed before intubation, although orotracheal intubation is rarely used in patients with tetanus. The most frequent indications for tracheostomy include:

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