Other aspects…….
· Clinical Features
The problem:
The
discovery of the organism causing tetanus by Nicolaier at the end of the 19th
century was quickly followed by a new concept of the pathogenesis of the
disease. A prophylactic approach was adopted
with the development of an anti toxin
as a passive immunising agent and the later development of toxoid
for active immunisation. In spite of
extensive cover of sections of the population as a result of the expanded immunisation programs which
reduced the global incidence of tetanus considerably, over fifty years after
the immunisation program got underway, over 1 million deaths due to tetanus
were reported in 1982. The problem of
the established case is still with us as it has been throughout the centuries.
Limited
resources:
In
the absence of specific treatment for the disease the introduction of muscle paralysis and artificial ventilation
for the symptomatic treatment of severe tetanus made a considerable difference to the mortality of the disease.
Unfortunately, in developing countries where the disease is widely prevalent,
this form of treatment requiring intensive care facilities is not freely
available and tetanus has been aptly described as a third world disease
which requires first world technology to treat. There is a continuing search for a treatment regime which
avoids the need for artificial ventilation. More so because even with intensive
care facilities there is still a high mortality amounting to even 30 - 40% in some centres due to cardiovascular
instability and lung complications associated with long term artificial
ventilation .
Brief Pathophysiology
Tetanus is a
toxic infection caused by the anaerobe clostridium tetani. Spores exist in the
soil and faeces and enter the body proliferating in devitalised tissue
producing exotoxins - tetanospasmin and tetanolysin. Tetanospasmin is a very potent neurotoxin and probably is
solely responsible for the disease. Tetanolysin has no recognised pathogenic
activity.
The toxin
circulates in the blood stream but does not enter the central nervous system
through this route as it cannot cross the blood brain barrier except at the
fourth ventricle. The toxin is exclusively taken up by the neuro muscular
junction and travels
via intra axonal transport at the rate
of 75-250 mm/day a process which takes 2 -14 days to reach the central nervous system.
The symptoms appear only after the toxin has gained access and caused blockade
of the presynaptic terminals of the inhibitory Renshaw cells and 1a fibres of
alpha motor neurons that handle gama
amino butyric acid (GABA) and glycine. This results in a the lack of inhibition
at brain stem and spinal cord level resulting initially in increasing resting
muscle tone or rigidity and later reflexes spread widely and inappropriately
resulting in spasms. The toxin binding appears to be irreversible, recovery
depending on the sprouting of new axonal terminals, probably explaining the
long duration of the disease which cannot be reduced by treatment.
Prior
to the early 1950s the main cause of death in tetanus was respiratory failure
secondary to spasms, obstruction by secretions, exhaustion and pulmonary
aspiration. The development of modern intensive care techniques, muscle
relaxation and artificial ventilation led to a dramatic decrease in these
deaths only to reveal severe cardiovascular complications with high mortality
due to autonomic dysfunction. Autonomic dysfunction is seen as increased basal
sympathetic activity and episodes of sympathetic overactivity (SOA) or “crises”
involving both alpha and beta receptors,
evidenced by high circulating levels of noradrenaline and loss of
inhibition of the adrenal medulla. During the crises, there is an outpouring of
catecholamines in amounts comparable with phaeochromocytoma. Other postulated
contributory causes are the direct inhibition by TT of the release of endogenous
opiates and the increased release of thyroid hormone
Clinical Features
The incubation
period ( injury to first symptom) is a reflection of the time taken for the
toxin production at the site of entry and its transport and uptake by the
central nervous system. The period
varies widely but usually ranges from 3 days to 3 weeks. With facial
injuries this time is shorter. Localised
or cephalic tetanus may occur first followed by generalized tetanus.
A history of
injury is present in the majority of cases but most wounds are of a trivial
nature. Tetanus may follow traditional practices like circumcision, ear
piercing and tattooing. The disease when
following intramuscular quinine injections has a significantly higher mortality than tetanus due to other
causes. The usual formulation available for intramuscular injection is acidic
(pH 2) and may cause local vasoconstriction and necrosis which lowers the redox
potential at the injection site providing a favourable millieu for rapid
sporulation and growth of the organism.
The mortality of tetanus in heroin addicts is also very high and it must be remembered that heroin is
often “cut” with quinine. Thus the
exclusion of tetanus due to the absence of an obvious portal of entry such as a
wound is unwise and the history of drug
addiction and injections of quinine are
relevant.
Early diagnosis is important to enable appropriate
therapeutic measures to be taken and to avoid life threatening respiratory
complications. Tetanus is unique in that diagnosis is based on purely clinical
observation and very little has been added to the description of the clinical
features through the centuries. Laboratory investigations are of no value except as a negative finding
The commonest
presenting symptom is trismus . Other
presenting symptoms could be backache
and abdominal pain but trismus soon follows. With severe tetanus all
muscles contract with the stronger overpowering the weaker. Rigidity progresses
in a descending manner, with dysphagia, risus sardonicus and neck stiffness, the short cranial nerves
being affected first. With severe tetanus there is opisthotonus, flexion of the
arms, extension of the legs, rigidity of the abdominal wall, followed by rigidity of the trunk and limbs.
A simple bedside test has recently been described to diagnose tetanus: the
spatula test. The posterior pharyngeal wall is touched with a spatula and a
reflex spasm of the masseters indicates a positive test. This occurred in 349
of the 350 patients with tetanus (sensitivity 94% and in no patient without
tetanus (specificity 100%)
Unusual forms
of presentation are seen in cephalic and local tetanus. Cephalic tetanus
presents after wounding of the head and neck with paralysis of the cranial
nerves. Facial paralysis and diplopia due to paralysis of the eye muscles are
the common findings. The diagnosis may
be missed initially but the other symptoms like trismus dysphagia and spasms follow very rapidly in
the majority of cases. Local tetanus is
an uncommon form with an incidence of about 2% with manifestations restricted
to muscles near the wound. The incubation period is long and spasms may spread
from one limb to the other .
The period
between the first symptom and the first
spasm is referred to as the onset time. Spasms
with intervening rigidity (being greater in the trunk than the limbs)
occur both spontaneously and on stimulation and varies in severity. Arching the
trunk - opisthotonus is a feature during the established disease. Periods of apnoea may occur due to spasm of
the intercostal muscles and the diaphragm. The differential diagnosis includes
acute local infections (dental or
masseter) with trismus and acute temperomandibular disease in the early
stages and meningitis and dystonic
reactions following neuroleptic drugs ( which typically involve lateral turning
of the head often with protrusion of the tongue - symptoms which are rarely
seen in tetanus).
Patient with
opisthotonus (courtesy : center for disease control)
Autonomic
dysfunction occurs in the more severe cases and sets in a few days after the spasms due to the slower intra
axonal transport to the lateral horn
cells. It consists of a basal sympathetic activity characterized by a resting tachycardia and depression of bowel
motility and bladder dysfunction. Episodes of severe sympathetic overactivity
(SOA) which includes fluctuating tachycardia, labile hypertension, sweating and
pyrexia takes place both with and without stimulation. Profuse salivation and
bronchial secretions due to increased parasympathetic activity also occur. All
these signs do not necessarily occur concurrently and its severity varies from
patient to patient.
Episodes of
bradycardia and hypotension some times lead to cardiac arrest, These signs have been explained on the basis
of increased parasympathetic activity, but many attribute it to sudden
withdrawal of sympathetic activity as the bradycardia does not always respond
to atropine. Cardiac arrest in tetanus has also been attributed to myocardial damage caused by high
catecholamine levels. and toxic damage to the brainstem.
Neonatal
tetanus presents most often about the seventh day of life with a short history
of failure to feed. Spasms are typical but the diagnosis can be mistaken for
meningitis or sepsis .
A useful
method of grading the severity of tetanus for the purposes of management and
study was devised by Ablett
Classification
Grade I (Mild)
- Trismus
Grade II
(Moderate) - Muscle rigidity
(trismus, dysphagia, risus sardonicus neck rigidity,
opisthotonus) and fleeting spasms not embarrassing respiration
Grade III
a (Severe) - Muscle rigidity
and severe spasms
Grade IIIb
(Very severe) Muscle rigidity, severe
spasms and autonomic dysfunction
The
severity of tetanus is usually predicted on the basis of the incubation period
and onset time as they are both inversely related to the amount of circulating
tetanus toxin. An incubation period of
less than 14 days and onset time of less than 48 hours is said to herald a
severe attack. Longer incubation and onset periods do not however always guarantee
a mild course of the disease.
TREATMENT (Note that magnesium sulphate has now greatly simplified the management)
Treatment of
tetanus consists of
1
Eradication of the organism
2. . Neutralization of the toxin
3. Symptomatic treatment of the
effects of the toxin; namely control of
a) muscle spasms
b) autonomic dysfunction
4. Supportive measures
5. Active immunization
Eradication
of the organism
The wound must
be cleaned with wide excision of
devitalised tissue under anaesthesia. Metronidazole is the antibiotic of choice
because of its effective penetration of
devitalised tissue and its activity
against anaerobes. Penicillin which was the traditional antibiotic for decades
is not recommended as it is a GABA antagonist and can aggravate spasms of
tetanus.
By the
time symptoms develop the frequent
absence of the wound or damaged tissue makes treatment based solely on adequate
wound care futile and urgent attention must be given to other measures
particularly to neutralisation of toxin.
Neutralisation
of toxin
Neutralisation
of toxin should be undertaken as early as possible since the toxin becomes
inaccessible to anti toxin after it enters the central nervous system. Human tetanus immune globulin (HTIG) i.m. should be injected in a dose of 500
units as the traditional much larger doses of 3000 - 5000 units are of questionable
benefit. In the absence of HTIG anti tetanus horse serum (ATS) after sensitivity
tests will suffice in a dose of 5000
units i.m. and 5000 infiltrated around the wound. HTIG or ATS should be injected within 24 hours of
diagnosis.
Attempts have
been made to inactivate the toxin that is bound to nervous tissue by administering
the anti toxin intrathecally thereby reducing the mortality from 70% to 18%. In
a comparison HTIG was given to 97 patients, in an intrathecal dose of 250 i.u. to 49 patients and an intramuscular
dose of 1000 i.u. to the remaining 48. There were only 3 deteriorations
(including one death ) with the intrathecal administration and 15
deteriorations (including 10 deaths)
with the intramuscular administration.
However a meta analysis on intrathecal therapy in neonatal tetanus
failed to provide convincing evidence that intrathecal therapy with either the
equine serum or HTIG is of major benefit in neonatal tetanus although clinically important treatment effects in
some subtypes cannot be excluded indicating
a need for more definite studies.
Symptomatic
measures
Early
Management
Control of
muscle spasms and autonomic dysfunction with maintenance of ventilation and
oxygenation while avoiding complications such as pulmonary aspiration is the
key to the management of tetanus.
During the
early stages, prior to spasms, mild sedation with oral diazepam is adequate.
Once dysphagia sets in, the development of spasms can be very rapid. It is often not sufficiently appreciated
that with the onset of spasms there is grave danger of life threatening
respiratory embarrassment and pulmonary aspiration of gastric contents if the trachea is not isolated in time. It must
be recognised that feeding via a nasogastric tube without tracheostomy carries
a high risk of pulmonary aspiration
with the onset of spasms. It is therefore recommended that if the incubation
period is less than 14 days , tracheostomy and insertion of a nasogastric tube
for feeding should be performed under
anaesthesia with the onset of dysphagia.. Mild sedation could be continued.
Control of Spasms
Spasms may lead to compromised ventilation, exhaustion, and often
aspiration of gastric contents, all of which are life threatening. Heavy
sedation was the mainstay of treatment but lost its importance with the introduction of muscle relaxants and
continued to be used only as an adjunct to provide patient comfort and tolerance to therapy.
Muscle
relaxants became the mainstay of
treatment of spasms in tetanus. Vecuronium is considered the drug of choice due
to the absence of cardiovascular effects but proves to be very expensive in the
long term. Atracurium has been used as an infusion with no serious cumulation
of metabolites. Pancuronium is better avoided in patients with severe
sympathetic activity, but these effects
are not very prominent in the dosages used, and is still popular in many
institutions due to the cost factor.
The disadvantage of muscle relaxants is the need for long term
artificial ventilation ( 2- 4 weeks)
which carries with it complications of pulmonary infection, barotrauma,
difficulty in weaning and deep venous thrombosis.
Dantrolene has
been used in place of muscle relaxants for the control of spasms in tetanus
without the need for artificial ventilation. It produces skeletal muscle relaxation by a direct action on
excitation contraction coupling, presumably by decreasing the amount of calcium
released from the sarcoplasmic reticulum.
Avoidance of the need for artificial ventilation is a tremendous
advantage, but dantrolene does not
suppress autonomic dysfunction and has
to be supplemented with heavy sedation in
the more severe cases. Dantrolene is an expensive drug , which, in the long term is a major disadvantage in developing countries where its effects
would be most advantageous.
The need for
heavy sedation is however rapidly re-gaining ground on the basis that muscle
relaxants alone with minimal sedation is associated with severe autonomic
dysfunction. A variety of drugs are used for this purpose, namely barbiturates,
diazepam, chlorpromazine morphine and recently even isoflurane and propofol.
In the absence
of glycinergic agonists, gama amino butyric acid agonists have been used for
the control of spasms. Diazepam as a GABA agonist has gained a traditional
place in the control of spasms in tetanus. As an adjunct to muscle relaxants it
was used in doses of 10 - 30mg 6 - 8 hourly. It has also been used
as the sole agent for the
control of spasms. We have used it in
doses of up to 15mg/hour, but the use of doses as high as 3400mg/day have been reported. Metabolic acidosis may
occur with these large doses probably due to the effects of the solubilising
vehicle propylene glycol. Ventilatory
support is not always necessary but the airway needs to be secured and the
prolonged after effects of these large doses
are a major disadvantage. Midazolam has also been used for the same
effect with less prolonged
duration of after effects, but its cost
is a limiting factor. We have used diazepam in combination with other
sedatives such as chlorpromazine and morphine to control spasms in severe
tetanus without the need for muscle relaxants or ventilation, but control
of basal rigidity is poor and mouth care and limb physiotherapy required
intermittent muscle relaxation. When given in large doses, diazepam prolongs
the stay in the ICU due to the presence of active metabolites with long half
lives. However in the more severe forms muscle relaxants become a necessary
adjunct .
Baclofen, a
GABA agonist, given by intermittent intrathecal injections to avoid artificial ventilation has been
reported, but ventilatory depression occurred in 5 out of the 10 cases possibly
due to overdosage. This
overdosage could be avoided with
continuous intrathecal infusion .
Practical considerations are the risk of infection with external infusions
devices (less costly) and the high cost
of the implantable infusion device.
Control of Autonomic dysfunction
A regimen is
required that will stabilise the cardiovascular system whilst preserving compensatory
mechanisms and avoiding sudden collapse and death. A variety of drugs have been
used with varying success and none of them entirely fulfils the above
criteria.
Two different approaches
have been used in the management of sympathetic over activity - peripheral
adrenergic blockade and suppression of the release of catecholamines with
sedation, both of which have been used as an adjunct to relaxants and
artificial ventilation.
Chlorpromazine
is a traditional sedative but was
specially useful due to its alpha blocking action. We used it in conjunction
with diazepam in doses of 50-100mg 8 hourly, but unacceptable hypotension
sometimes occurred.
Propanolol,
with or without concomitant alpha blockers, was the first drug used and was
reported as effective; but in the late
1970s several workers reported fatal cardiovascular failure and irreversible
cardiac arrest in patients treated with propranolol. We ourselves had a similar
experience; namely bouts of severe
bradycardia and one case of irreversible cardiac arrest in a patient treated
with propranalol led us to abandon this treatment. Concern over unopposed alpha
stimulation led to the addition of specific alpha blockers and then to the use
of labetalol which (combined alpha and beta block) was used successfully, only to be implicated in irreversible
cardiac arrest. The short acting beta
blocker esmolol has been useful in suppressing crises but this does not solve the problem as
the catecholamine levels remain high.
The use of
adrenergic blockade without the preservation of some response to changes in
sympathetic activity can therefore be effective, but unpredictably dangerous.
The combined alpha and beta blockade effectively denervates the cardiovascular
system rendering the pressure support difficult during hypotensive episodes.
The release of catecholamines is unaffected and these high levels can cause
myocardial damage, which could be implicated in the irreversible cardiac
arrest.
With the
recognition of sympathetic over activity and the danger of using adrenergic
blocking agents, heavy sedation has been re-introduced in an attempt to block the exaggerated
response to stimuli , and thus control the endogenous autonomic dysfunction by
suppressing catecholamine release. This
has been recognised as a more
logical method of suppressing autonomic dysfunction.. Varying degrees of
success have been claimed for a variety of drugs such as barbiturates, chlorpromazine, benzodiazpines,
and volatile anaesthetics. The use of
morphine for the control of autonomic dysfunction has been reported as
effective, and was probably due to replacement of the deficiency in
endogenous opioids found in tetanus. We
have used it over the last five years and found it to be very effective.
The only disadvantage is the depression of bowel motility which limits the use
of enteral feeding.
However heavy sedation does not
reliably control the sympathetic over activity in all cases especially that which
occurs in response to stimulation. Other drugs such as magnesium sulphate and
clonidine have been used as an adjunct
to heavy sedation.
The difficulty
in finding a drug which controls autonomic dysfunction in all cases of tetanus
could be due to the variation in plasma concentrations achieved, individual
variation in response or the varying degrees of severity of the disease. As yet
no single drug which controls spasms and autonomic dysfunction in all patients
has been found and the search continues.
A regime which
controls spasms without the need for artificial ventilation is a much sought
after treatment modality in tetanus. In 1996 we commenced the use of
intravenous magnesium sulphate infusions as the sole agent for the
control of spasms in patients with severe tetanus. We were able to control spasms and minimise rigidity without the
need for artificial ventilation. Since we used it as the sole agent (without muscle relaxants and heavy
sedation) it was possible to titrate the dose against clinical signs (control
of spasms and rigidity, with
preservation of the patellar reflex)
which made it much easier than titrating the dose against serum
magnesium levels. With this method of titration magnesium concentrations were
found to be maintained within the therapeutic range. The striking features of
magnesium therapy was that it could be titrated to control spasms without
compromising ventilation as hypoventilation occurred at higher concentrations
than that required to control spasms. The absence of sedation and immobility
avoids the danger of deep vein thrombosis and helps considerably in overall
management.
Magnesium has
the special advantage of combining
control of spasms by neuromuscular blockade without the need for
artificial ventilation and cardiovascular instability by suppressing
catecholamine release. Whether this form of therapy will control autonomic
dysfunction in the more severe forms of tetanus is still to be seen.
Supportive measures:
The intensive
care management of tetanus requires not only the provision of ventilatory
support but also the support of all organs systems which are dysfunctional as a
result of the disease and its therapy. This includes respiratory complications
(from aspiration of oral and gastrointestinal contents), cardiovascular
dysfunction, depression of gastro intestinal motility, and now the recognised
effects of immobility namely thrombo embolism, fluid retention due to
inappropriate secretion of anti diuretic hormone, and nosocomial infections
from prolonged invasive instrumentation.
Airway
Early
tracheostomy helps to isolate the trachea and facilitate ventilation without
undue stimulation of the upper airway. The endotracheal tube inserted as an
emergency is best converted to
tracheostomy as soon as possible for the incidence of complications with long
term endotracheal intubation are often high and clearance of secretions is
easier with tracheostomy. Careful
management of the cuff allowing a small
leak must be ensured at all times.
Care of the lung
Regular
physiotherapy (lung and limbs) and tracheal suction are mandatory, as lung
complications are a common cause of morbidity and mortality. Secretions and
salivation are special problems and are evidence of increased parasympathetic activity. Nebulisation with ipratropium can help to reduced bronchial
secretions considerably.
The staff must
take special precautions to prevent nosocomial infections and prophylactic
administration of thrombolytic therapy is important to avoid deep vein thrombosis.
Enteral Feeding
Should be
commenced as soon as possible through the naso gastric tube since nutrition is
particularly important during long term ventilation.
Mortality
figures depend on the availability and quality of intensive care, and the age of
the patient.. A mortality of 10% is often quoted as reasonable but is in
fact higher in most centres.
Active immunisation
The disease does not confer any significant
immunity and all patients should be actively immunised, the first dose being
given as soon as the diagnosis is made. The second dose, given one month later
, can often be given before discharge, but the patient must be requested to
come for the third dose in a 6 month follow up. This also offers an opportunity to review the patient for any
complications due to long term tracheostomy and immobilisation.