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.