Discussion:
Tetanus is still a global concern since the World Health Organization
reported 14751 tetanus cases in 2019 (8). Generalized tetanus was the
most common type, accounting for about 80% of patients (10). It has
been suggested that ICU admission results in better monitoring, and
timely diagnosis of complications will reduce morbidity and mortality
rates (5, 11). Although there are some protocols for tetanus management,
there is a lack of substantial evidence for tetanus management
strategies (1, 11). Hence, the management of tetanus is challenging even
for the most experienced physicians.
In this case, although we administered tetanus immune globulin (500 IU)
and intravenous metronidazole on the first day of admission, the spasms
continued to worsen over the first 5 to 10 days of hospitalization. This
might be due to the toxin that had already entered the motor neurons and
was progressing toward the central nervous system (6). It has been
reported that tetanospasmin inhibits the action of enkephalins, which
may play a role in modulating the autonomic nervous system (12).
Midazolam, morphine sulfate, and MgSO4 were administered from the first
day of admission to control muscle spasms and pain. There are several
reports about the role of MgSO4 in patients with tetanus. It might be
used to resolve muscle spasms and autonomic instability (including
hypertension and tachycardia) and reduce the need for benzodiazepines
and neuromuscular blockers. On the other hand, some studies suggest that
MgSO4 has no significant effect on mortality and should not be used as
monotherapy in these patients (13).
Although no preferred combination therapy is available thus far, some
studies suggest the addition of propofol, neuromuscular blockers, or a
combination of both when there was no adequate clinical response to
benzodiazepines (7, 14). Therefore, we added atracurium and then
propofol because of the patient’s resistant spasm and high sensitivity
to any sensory stimulus.
Intrathecal baclofen has been successfully used in patients with spasms
that are resistant to neuromuscular blocking agents. It seems that
intrathecal baclofen could shorten the duration of mechanical
ventilation and reduce the rate of mortality (15), but since intrathecal
baclofen was not available in our setting, we decided to administer oral
baclofen.
Since the probability of propofol infusion syndrome was high, we decided
to add intravenous phenobarbital to the previous medications. There are
some case reports supporting the use of phenobarbital in generalized and
neonatal tetanus, although some of them have shown no mortality benefit
(16). A meta-analysis of studies on children with tetanus reported
diazepam alone is more beneficial on controlling tenues and reducing
mortality than if it is combined with phenobarbital (RR of death 0:36;
95% CI 0:15 to 0.86; risk difference - 12:22; 95% CI -0.38 to - 0.06)
(17). However, the combination of diazepam and phenobarbital compered to
diazepam alone has demonstrated a significantly milder clinical course
and shorter hospitalization (18). This evidence confirming the efficacy
and safety of phenobarbital in tetanus management, which suggests adding
phenobarbital to primary treatment of severe tetanus could be a
favorable choice.
On day 10 of ICU admission, the patient showed a significant reduction
in clinical manifestations, although intermittent muscle spasms
continued until day 32. Due to the use of combination therapy to manage
severe muscle overactivity in this case, it is not clear which drug
yielded the most clinical benefit. On the other hand, due to the
patient’s severe pain and spasms and to follow the ethical
considerations, we decided to add medications as soon as possible in the
failure of a complete response to first-line therapy. Since tetanus
infection does not provide natural immunity, patients need a full course
of vaccination. Our patient received one dose of Td vaccination on his
first admission and the second dose during discharge. The next dose
should be administered 6 to 12 months later. Although it has been
suggested that vaccine-naïve patients should receive at least one dose
of Tdap vaccination (19), due to the unavailability of Tdap in our
region we considered Td for all three doses.