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These guidelines are provided by the ABSTRACT of experts to develop these guidelines,
Associação de Medicina Intensiva which are based on the best available
Brasileira (AMIB). Although tetanus can be prevented evidence for the management of tetanus
by appropriate immunization, accidental in patients requiring admission to the
tetanus continues to occur frequently in intensive care unit. The guidelines discuss
underdeveloped and developing countries. the management of tetanus patients in
Tetanus mortality rates remain high in the intensive care unit, including the use
these areas, and studies regarding the best of immunoglobulin therapy, antibiotic
therapy for tetanus are scarce. Because of therapy, management of analgesics,
the paucity of data on accidental tetanus sedation and neuromuscular blockade,
and the clinical relevance of this condition, management of dysautonomia and specific
the Associação de Medicina Intensiva issues related to mechanical ventilation
Brasileira (AMIB) organized a group and physiotherapy in this population.
INTRODUCTION
autonomic nervous system usually begin by the second Articles retrieved through the literature search
week as a typical autonomic dysfunction syndrome that is were critically analyzed and categorized according to
characterized by labile hypertension, tachycardia, cardiac their evidence level, as shown in Table 1. Therefore,
arrhythmias, peripheral vasoconstriction, diaphoresis, recommendations were given a character and a number,
pyrexia and eventually hypotension and bradycardia, reflecting both the level of evidence and the strength of
suggesting that the sympathetic and parasympathetic the recommendation.
systems are affected.(3)
The severity of accidental tetanus depends on the Table 1 - GRADE System
distribution of muscle spasms, with localized cases 1. Strong recommendation
involving a few muscle groups and generalized cases 2. Weak recommendation.
involving the entire skeletal musculature.(7) A: Randomized and controlled trials.
Because of the paucity of data on tetanus and the B: Randomized and controlled trials with limitations leading
clinical relevance of accidental tetanus, the Associação de to downgrading of the evidence level or well performed
Medicina Intensiva Brasileira (AMIB) organized a group of observational studies with an upgraded evidence level.
experts who developed these guidelines, which are based on C: Well conducted observational studies.
the best available evidence for the management of tetanus D: Expert opinions or case series.
in patients requiring admission to the intensive care unit.
The guidelines discuss the management of tetanus patients The questions and search strategies were discussed
in the intensive care unit (ICU), including the use of and distributed for the group members during the
immunoglobulin and antibiotic therapies, the management first meeting. Later, each response was forwarded for
of analgesia, sedation and neuromuscular blockade, the discussion via electronic media. Next, the board of experts
management of dysautonomia and mechanical ventilation gathered in person; the recommendations and rationales
and physiotherapy issues in this population. were discussed and approved by consensus. No voting
methodology was used. The final document was approved
METHODS by all participating experts before its publication.
The questions were prepared and revised by the group Description of the evidence collection method
of experts. The primary aspects of the treatment of tetanus The primary literature search was conducted on
were considered, and the PICO concept was used, where MEDLINE, which was accessed via the PubMed service.
P stands for the target population, I for the intervention, Searches were based on questions that were structured
C for the control or comparative group and O for the according to the P.I.C.O. methodology. The search
clinical outcome. strategy used for answering each question is shown, along
The recommendation degrees are provided by the GRADE with the recommendation and rationale supporting the
(Grades of Recommendation, Assessment, Development intervention. Additionally, a generic search using the
and Evaluation) system.(8) This system is based on assessment keyword ‘tetanus’ was conducted using the Scientific
of the quality of the evidence followed by a risk/benefit Electronic Library On-line (SCIELO) and Cochrane
assessment. Based on this analysis, the recommendations Collaboration databases.
were categorized as STRONG (grade 1) or WEAK (grade 2),
as shown in table 1. A strong recommendation either for or TETANUS MANAGEMENT RECOMMENDATIONS
against a given intervention means that the desirable effects of
this intervention clearly outweigh its untoward effects or vice 1. Does admission to the intensive care unit impact
versa. A weak recommendation either for or against a given tetanus patients’ morbidity and mortality?
intervention means that the benefits of this intervention
are likely to outweigh its risks and burdens (or vice versa), Search strategy
but the group is not confident in the recommendation Tetanus AND (critical care OR intensive care OR ICU
because of insufficient or poor quality evidence. In practical OR critically ill).
terms, a strong recommendation could be interpreted
as “recommended to be done (or not recommended).” We recommend management in the intensive care
Conversely, a weak recommendation could be interpreted as unit (ICU) for patients with moderate and severe
“suggested (or not suggested).” accidental tetanus for better monitoring, rapid
detection of complications and intensive care by a than patients managed in regular wards.(21) Patients were
trained team, regardless of their age group (1B). transferred to the ICU only when more severe disease or
We suggest ICU admission for patients with mild complications occurred, while mild cases were treated
tetanus, particularly if poor-prognosis risk factors are outside the ICU. These patients had lower risks of
present (2C). respiratory and hemodynamic complications, which are
We suggest that in cases with limited ICU bed currently the main causes of death in tetanus patients.
availability, patients who have mild tetanus without The management of mild tetanus cases in regular
poor-prognosis risk factors can be managed outside the wards may be an alternative in cases of limited ICU bed
ICU in regular wards staffed by personnel experienced availability; patients may be admitted to the intensive
in the care of patients with tetanus, provided that such care unit when poor prognostic signs are identified at
patients are admitted to the ICU if worsening of their admission. Risk factors include: short incubation time (<
clinical condition is detected (2D). 10 days), short progression time (<48 hours), age above
60 years, severe comorbidities, or infective, respiratory,
Rationale hemodynamic or renal complications at the time of
Several studies emphasize the importance of admitting admission.
tetanus patients, especially those with more severe clinical However, most of the experts recommend admitting all
presentations, to intensive care units. ICU admission is patients to the ICU immediately following a diagnosis of
particularly beneficial for elderly patients, whose mortality accidental tetanus, regardless of the disease severity, due to
rates are higher.(1,2,9-18) In the ICU, appropriate monitoring the risk of rapid disease progression and complications.(12,19)
and quick detection of complications can be performed by
a trained multidisciplinary team.(12-14,17,19,20) 2. Is a clinical strategy of grading the severity of
We highlight five studies that showed reduced disease relevant to the management of tetanus patients?
mortality after ICU admission in tetanus patients. In
Japan, a decrease in mortality from 40-50% for patients Search strategy
treated between 1940 and 1970, to 20% for patients Tetanus AND (severity OR grading OR classification OR
treated between 1971and 1980, and 10% for patients severity score).
treated between 1981 and 1982 was shown.(15) In Spain,
mortality decreased from 58.3% to 24.6% between We suggest that each service should routinely use
1968 and 1990;(10) in Venezuela, mortality dropped from one of the several accidental tetanus disease severity
43.58% to 15%;(2) and in India, mortality decreased from classification currently available in the medical literature.
70% to 23% of severe tetanus cases.(14) A Brazilian study Patients should be categorized upon admission due to
from Recife-PE showed a drop from a mortality of 35% in the prognostic value of disease severity classification.
1631 patients treated outside of the ICU between 1981- The most severe forms require more aggressive therapy
1996 to 12.6% in 638 patients treated after the ICU was and are more frequently associated with complications
established (p < 0.001).(18) and increased mortality (2D).
However, several authors have persistently high
mortality rates in spite of ICU care.(4,21-23) This finding Rationale
suggests that in addition to the ICU facility itself, trained Several authors have proposed severity grading
staff and advanced technology appropriate to such methods based on clinical parameters (such as intensity
severely ill patients’ needs are important. This hypothesis of the muscle contractures, spasm frequency, and response
is supported by a Brazilian study in which the mortality to muscle relaxant drugs) and/or prognostic factors (such
rate dropped from 36.5% before 1993 to 18% after 1993 as incubation and progression times). Classification
(p=0.002) after the quality of care improved and a strict systems that are based only on clinical data, when used
treatment protocol was adopted. This finding was observed repeatedly over time, describe whether the symptoms are
despite differences in the second group that included improving or worsening. The patients’ changing from
longer ICU stays, increased use of benzodiazepines, one clinical form to another can predict the patients’
neuromuscular blockade and mechanical ventilation, and responses to therapeutic measures and the outcome of the
a higher rate of infectious complications.(1) illness.(6) Therefore, patients may be divided into grades
Another study showed that patients admitted to the (numerically) or clinical forms (mild to very severe),
ICU had worse outcomes and higher mortality rates depending on the classification used.(5,6,24-26)
Independent of the categorization used, patients seen between higher and lower doses.(42-44) Recent data
classified as having more severe disease have a worse suggest doses between 500 and 1,000 IU/kg.(7,45) There is
prognosis and are more likely to develop respiratory, also no consensus regarding the dose of specific human
infectious and cardiovascular complications. Such patients immunoglobulin for the treatment of tetanus. The doses
therefore require a more aggressive approach.(5,6,24,25,27-33) used range from 500 IU to 10,000 IU.(1,44-46) There are
Mortality is also related to the severity classification. no randomized clinical trials comparing different doses
Although the mortality rate of mild tetanus is low, patients and tetanus morbidity and mortality. In an observational
with severe and very severe disease are more likely to die analysis by Blake et al.,(46) no difference was found between
and should be intensively monitored and treated. (23,26,34-39) doses of 500 and 10,000 IU.
Randomized clinical trials have been conducted both 7. Does the antibiotic schedule (either metronida-
in children and adults. The first adult studies, which zole, crystalline penicillin or benzylpenicillin) impact
used equine anti-tetanus serum, failed to show a benefit tetanus patients’ morbidity and mortality?
from this procedure. Additionally, such complications as
meningeal irritation were seen, requiring the concomitant Search strategy
use of systemic or intrathecal corticosteroids.(48) Tetanus AND [antibiotic OR antimicrobial OR
After specific human anti-tetanus immunoglobulin metronidazole OR penicillin OR doxycycline].
became available, new intrathecal trials were conducted,
starting in the 1980s. These studies showed a benefit in We recommend using antibiotics active against
terms of some secondary outcomes, such as shortened Clostridium tetani with the goal of eradicating it from
duration of muscle spasms and length of ICU stay. the inoculation focus (1C).
However, intrathecal antitoxin had no impact on We suggest either metronidazole or penicillin can be
mortality.(49-52) Most patients included in these studies used; neither of these drugs has proved to be superior
had mild or moderate tetanus; additionally, treatment to the other one (2B).
methods and observation times were quite heterogeneous. We suggest using other antibiotics only if the use
The antitoxin doses in these studies were also highly of metronidazole and/or penicillin is contraindicated
variable, ranging from 200 IU to 1,000 IU. When patients (2D).
with severe tetanus were analyzed separately, no benefit
was shown, even for secondary outcomes.(49,50) Therefore, Rationale
this procedure is not recommended, especially in cases of Although no clinical trials support a clinical benefit of
severe tetanus. antibiotics for Clostridium tetani eradication, antibiotics
are always indicated for the treatment of tetanus patients.
6. Does early debridement of the wound impact (7)
This goal of this treatment is eradication of the toxin-
tetanus patients’ morbidity and mortality? producing bacteria from the inoculation focus.
Benzylpenicillin was the first antibiotic used for treating
Search strategy tetanus. However, penicillins produce a non-competitive
Tetanus AND [debridement OR focus control]. The and voltage-dependent inhibition of GABA-A receptors,
analysis of the articles showed no comparative clinical trial suppressing the postsynaptic inhibitory response,(56)
of early or late wound debridement. and may theoretically increase the excitatory effects of
tetanospasmin.
Inoculation focus debridement is recommended (1D). Metronidazole is a safe alternative for the treatment of
We suggest performing this procedure 1 to 6 hours tetanus. This drug is affordable, highly bioavailable, has
after immunoglobulin administration, given that the good gastric and rectal absorption and has bactericidal
best timing for this procedure has not been established action against anaerobic bacteria. Additionally, gastric
(2D). pH interferes little with metronidazole (compared
to erythromycin and doxycycline) and undergoes no
Rationale enzymatic inactivation (as do the β-lactam antibiotics).(57)
Debridement of the C. tetani inoculation focus has been No evidence is available on the superiority of one
performed since the first tetanus cases were described. The drug over the other,(54,58,59) although some data show more
rationale for this procedure is based on the presumption benefits from the use of metronidazole.(58,59)
that toxin production is maintained for as long as C. tetani Little evidence is available regarding the clinical
is present and that toxin production could be stopped use of other antibiotics for the eradication of C.
by removing the bacteria.(40,53,54) No studies are available tetani. Such alternatives as erythromycin, tetracycline,
comparing early versus late debridement of the inoculation doxycycline, ceftazidime, vancomycin, clindamycin
focus. The recommendation for performing debridement and chloramphenicol are only justifiable if penicillin or
1 to 6 hours after systemic HATIG or ATS is administered metronidazole are not available.(7)
is based on the rationale that this interval would allow
appropriate toxin neutralization at the wound, thereby 8. Compared to placebo, does vitamin C have an
preventing toxin dissemination during manipulation of impact on the morbidity and mortality of severe
the wound.(55) tetanus patients?
may represent an alternative to diazepam, and continuous mechanically ventilated patients with severe tetanus.
infusion of midazolam does not have the same adverse No randomized and controlled studies are available
effect profile of diazepam. However, midazolam may to assess the possible positive or negative effects of this
cause delirium, is more expensive, and has more frequent association in tetanus patients. The vast majority of the
hemodynamic effects. relevant articles are case reports or small patient series.
Baclofen is another therapeutic alternative to diazepam. Five retrospective studies include most of the assessed
This drug is a GABA-ergic receptor agonist, which inhibits patients.(1,13,17,82,83)
the presynaptic elimination of acetylcholine, leading to In the assessed articles, pancuronium was the most
muscle relaxation. Because baclofen does not cross the commonly used drug followed by vecuronium, atracurium
blood-brain barrier, intrathecal administration of baclofen and rocuronium. This finding may be explained by the
may optimize its effect in tetanus. This drug may be given timing of the introduction of these drugs into clinical
as a continued infusion or intermittently; the maximal practice. Until the early 1980s, only pancuronium
daily dose is 2 mg. The infusion may be started at 20 µg/ was available; the other drugs were introduced during
hour and progressively increased every 4 to 8 hours until the 1980s.(84) Therefore, recommendations for the use
the desired effects are obtained. The infusion rate may be of neuromuscular blockers in tetanus patients are not
increased by 8-10 µg/hour. The maximum treatment time different from commonly used guidelines for critically ill
reported in the literature is 3 weeks.(72) Classical side effects patients.(84)
including drowsiness, vertigo, nausea and confusion are Several adverse effects associated with the use of curare
not relevant in tetanus patients. Eventually, hypotension drugs should be considered. These effects are usually
and delirium may occur.(73) However, there is a risk of caused by prolonged immobility and may lead to muscle
infection associated with a long-term epidural catheter, atrophy, eye injuries, nerve injuries due to compression
even when it is tunneled.(72) Baclofen is not available as and deep vein thrombosis.(85) There is evidence that
an intrathecal formulation in Brazil. Therefore, its use is prolonged muscle blockade may result in prolonged
limited to oral administration during the convalescence palsy and weakness in severely ill patients. These effects
phase of tetanus; doses can range up to 60 mg/day. have been associated with eventual overdose, which is
a preventable inconvenience with appropriate clinical
12. Is the use of neuromuscular blockers associated monitoring.(85,86) The duration of neuromuscular blocker
with improved clinical outcomes in severe tetanus administration should be as short as possible. The use of
patients under mechanical ventilation? protocols based on monitoring of the desired blockade
can reduce the mechanical ventilation time, the length of
Search strategy ICU stay and costs.(87,88)
Tetanus AND [neuromuscular blockade OR pancuronium
OR vecuronium OR atracurium OR rocuronium OR 13. Is the use of any specific drug for analgesia and
cisatracurium] sedation of tetanus patients associated with improved
outcomes?
We suggest using neuromuscular blockers, preceded
by appropriate sedation and analgesia, to provide muscle Search strategy
relaxation and control spasms in patients with severe Tetanus AND analgesia AND sedation AND outcome,
tetanus who are undergoing mechanical ventilation and resulting in one single article. The search was extended
are refractory to other muscle relaxants (2D). using the following keywords: tetanus AND outcome AND
We suggest that choice of drug should follow the (sedation OR analgesia OR clonidine OR dexmedetomidine
same criteria as for other critically ill patients (2D). OR propofol OR opioids OR morphine OR fentanyl OR
remifentanyl OR phenobarbital OR anesthesia), tetanus
Rationale AND sedation and tetanus AND analgesia.
The drugs of choice to provide sedation, spasm
control and muscle relaxation in tetanus patients are We suggest analgesia and sedation of tetanus patients
benzodiazepines with opioids, which are used to provide should be performed using opioids with central alpha
appropriate analgesia. Even in high doses, this combination agonists and/or propofol, although no evidence for the
may be insufficient to control muscle spasms, and the use superiority of any of the several reported strategies is
of neuromuscular blockade may be required, especially in available (2D).
100 years(125) and has several potentially useful features undergoing prolonged mechanical ventilation.(130)
for the management of severe tetanus. These features No articles have been published on the role of
include muscle relaxation, vasodilation, reduced heart rate physiotherapy in tetanus patients. However, there
and reduced systemic catecholamine levels.(109,114,126,127) is no evidence that physiotherapy in these patients,
Magnesium may therefore be an effective adjunct therapy if appropriately performed, causes adverse effects.
for muscle spasm and autonomic dysfunction control. Therefore, physiotherapy should be performed according
Several case reports and series have been published to each site’s protocol. Passive motor physiotherapy
that suggest benefit from the use of MgSO4(114,126,128) may prevent joint deformities and muscle shortening.
However, only one randomized, double-blind clinical Also, orthopedic splints may be used to maintain the
trial comparing MgSO4 and placebo has appropriately physiological position of the feet, preventing deformity.
addressed this issue. In an observational prospective Because any stimulus may trigger spasms in tetanus
study, Attygale et al. showed that MgSO4 reduced the use patients, analgesia/sedation and/or neuromuscular
of sedatives and neuromuscular blockers and decreased blockage should be increased before physiotherapy and
ventilatory support requirements when administered for returned to previous levels after the therapy session.
7 days.(127)
These findings were partially confirmed in a CLOSING REMARKS AND FUTURE
randomized, placebo-controlled clinical trial conducted PERSPECTIVES
in 2006.(129) In this study, 256 patients were randomized
to receive continued intravenous MgSO4 infusion or Although it is preventable through vaccination,
the placebo for 7 days. A loading dose of 40 mg/kg for accidental tetanus remains a common problem in
30 minutes was used followed by a 2 g/hour infusion. underdeveloped and developing countries and has
The randomization was appropriately performed via a extremely high mortality rates. Most evidence regarding
computer-generated randomization list, and the blinding the optimal management of tetanus comes from anecdotal
was appropriate. No significant difference was observed reports and case series. This report is the first initiative
in the primary endpoint (requirement of ventilation to gather experts for a critical review of the literature
support during the first 7 days) with an OR of 0.71 regarding adult tetanus patients in the intensive care
(95% CI 0.36-1.40). However, a significant difference unit setting in order to provide specific guidelines for the
was found in the secondary endpoints, i.e., reduced management of tetanus.
needs of benzodiazepines, neuromuscular blockers and Despite advances in the knowledge of the
verapamil, which were considered to be the treatment pathophysiology of tetanus and the development of
of choice for dysautonomia in this study location. This specific therapies for the disease, certain aspects of the
result suggests a role for MgSO44 as a potential adjuvant ICU management of tetanus patients need to be more
for control of spasms, and it may also be useful agent for objectively evaluated. We described a number of these
the management of autonomic dysfunction in patients issues and attempted to suggest interventions that can
with severe sepsis. affect the outcomes of patients with tetanus based on a
critical assessment of the scarce literature and the experts’
17. Does respiratory physiotherapy in severe tetanus experience regarding this subject. However, definite
patients impact outcomes? answers regarding the usefulness of specific strategies in
the intensive care unit management of accidental tetanus
Search strategy in adults will only come from collaborative clinical trials
Tetanus AND [physiotherapy OR passive mobilization]. and clinical investigation networks on both the national
and international levels.
We suggest motor and respiratory physiotherapy in
mechanically ventilated tetanus patients (2D).
We suggest an increase in analgesia/sedation and/or RESUMO
neuromuscular blockade before physiotherapy (2D).
O tétano acidental, a despeito de ser uma doença prevenível
Rationale por imunização, ainda é frequente nos países subdesenvolvidos e
em desenvolvimento. Sua letalidade ainda é elevada e os estudos
Physiotherapy is part of the multidisciplinary care of
sobre a melhor forma de tratamento são escassos. Tendo em vis-
several types of intensive care unit patients, e.g., patients
ta esta escassez e a importância clínica dessa doença, um grupo aspectos relativos à admissão do paciente tetânico na unidade de
de especialistas reunidos pela Associação de Medicina Intensiva terapia intensiva, tratamento com imunoglobulinas, tratamento
Brasileira (AMIB), desenvolveu recomendações baseadas na me- antibiótico, manejo da analgossedação e bloqueio neuromus-
lhor evidencia disponível para o manejo do tétano no paciente cular, manejo da disautonomia e especificidades na ventilação
necessitando cuidados intensivos. As recomendações incluem mecânica e fisioterapia nesta população especial.
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