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\begin{document}

\title{Successful management of severe generalized tetanus in a 23-year man
with Phenobarbital adjuvant: a case report}



\author[1]{Arezoo  Ahmadi}%
\author[1]{Elahe Karimpour-razkenari }%
\author[1]{ramin ansari}%
\author[1]{Mahforouzalsadat  Marashi}%
\author[1]{hamidreza sharifnia}%
\author[1]{Atabak  Najafi}%
\author[1]{Mojtaba Mojtahedzadeh}%
\affil[1]{Tehran University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\textbf{Successful management of severe generalized tetanus in a 23-year
man with Phenobarbital adjuvant: a case report}

Arezoo Ahmadi\textsuperscript{1}, Elahe
Karimpour-Razkenari\textsuperscript{2}, Ramin Ansari\textsuperscript{2},
Mahforouzalsadat Marashi\textsuperscript{3}, Hamidreza
Sharifnia\textsuperscript{1}, Atabak Najafi\textsuperscript{1}, Mojtaba
Mojtahedzadeh\textsuperscript{2}*

1 Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran
University of Medical Sciences, Tehran, Iran

2 Department of Anesthesiology and Critical Care, School of Medicine,
Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.

3 Department of Infectious Disease and Tropical Medicine, School of
Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran,
Iran.

Corresponding author: Mojtaba Mojtahedzadeh; Pharmacist; Board Certified
of Pharmacotherapy Specialty; Fellowship of Critical Care
Pharmacotherapy; Department of Clinical Pharmacy, Tehran University of
Medical Sciences

mojtahed@tums.ac.ir

Sina Hospital, Imam Khomeini St, Hasanabad Square, Tehran, Iran

Tel: +982164120

Postal code: 1136746911

Fax number: 00982166348587

\textbf{Abstract}

With a mortality rate of up to 50\%, generalized tetanus is still a
global concern, especially in low and middle-income countries. A
23-year-old man from Afghanistan was admitted to Sina Hospital,
affiliated with Tehran University of Medical Sciences, with the chief
complaint of generalized severe spasms and lockjaw. The patient had a
history of skin lesions and had never been vaccinated against tetanus.
He admitted to the intensive care unit after intubation in emergency
room, with diagnose of severe generalized tetanus. After receiving
tetanus immunoglobulin and intravenous metronidazole, a combination
therapy of midazolam, propofol, atracurium and morphine was
administered. Due to the refractory muscular spasms intravenous
phenobarbital started and little by little recovery was achieved. With
no symptom recurrence, after receiving the first 2 doses of the Td
vaccine, the patient was discharged on day 42.

\textbf{Keywords:} Tetanus, phenobarbital, Intensive care

\textbf{Introduction:}

Tetanus is caused by Clostridium tetani and has a mortality rate of
4.2\% to 50\%, but it is a vaccine-preventable disease (1). Higher
mortality rates have been reported from centers with limited intensive
care and ventilator support (2). Despite the dramatic reduction in the
prevalence of the disease thanks to vaccination programs, tetanus
remains a global problem, particularly in low and middle-income
countries due to lack of vaccination or not receiving the booster dose
(3, 4).

As a toxin-producing, anaerobic gram-positive spore-forming bacterium,
Clostridium tetani produces tetanolysin and tetanospasmin. Besides the
role of tetanolysin in intensifying wound damage and providing anaerobic
condition for bacterium growth, most of the clinical manifestations of
tetanus result from tetanospasmin, which inhibits gamma amino butyric
acid (GABA)-ergic and glycinergic neurons (5, 6).

The diagnosis of generalized tetanus is based on the history of the
injury and clinical features (7). Due to the limited capacity for
clinical trials and available management options, there is still
limitations in evidence-based management strategies for the disease (8).
Nevertheless, treatments such as early tracheostomy and administering
benzodiazepines, magnesium sulfate, and morphine are effective and
recommended as first line therapy alongside supportive care. Also,
admission to intensive care unit (ICU) is offered for patients with
high-risk tetanus (4). Phenobarbital is a barbituric acid derivative
that acts as a non-selective central nervous system inhibitor by
mimicking the action of GABA in the brain. It enhances the effects of
GABA by facilitating the passage of Cl through Cl channels in GABA
receptors. Therefore, it appears that phenobarbital may be able to
reverse the inhibitory effects of tetanospasmin on the GABA receptor.

In this paper, we introduce a case of severe generalized tetanus with
respiratory failure, whose spasm did not improve with full doses of
benzodiazepines and muscle relaxant agents, but it was finally managed
with propofol and phenobarbital.

\textbf{Case report:}

A 23-year-old man (wt= 70kg), construction worker from Afghanistan with
no notable medical history, was admitted to the emergency department of
Sina hospital, affiliated with Tehran University of Medical Sciences.
The patient presented lockjaw leading to dysphagia and intermittent
intense muscular spasm in the upper and lower limbs. 3 days before
admission, a nail stuck into his right sole. The patient was not
vaccinated against tetanus. On the admission day, he had stable
hemodynamics (BP = 121/79 mmHg, HR = 90 beat/min, RR = 21 breath/min,
SPO2=98 \%, Temperature = 37.5 \selectlanguage{ngerman}°C oral) and normal laboratory results
(CBC, ESR, CRP, LFT, Cr, BUN, VBG, and serum electrolytes). He received
1 vial (250 IU) of tetanus immune globulin and the first dose of the Td
vaccine intramuscularly before leaving the emergency department with
personal consent. Three days later he was readmitted to the emergency
department, and presented loss of consciousness (GCS= 10) and
generalized severe spasm and rigidity in the lower and upper limbs.
Other clinical manifestations included sustained spasms of the facial
muscles (Risus sardonicus), severe contractions of masseter muscles
(lockjaw), and sweating, and his hemodynamics were unstable (BP = 178/90
mmHg, HR = 180 beat/min, RR = 45 breath/min, SPO2=85 \%, Temperature =
38.5 °C). According to the Ablett classification of tetanus severity
(9), the patient's condition was very severe. The patient was intubated
in the emergency department and admitted to the ICU. His laboratory
results upon admission to the ICU and discharge time are given in Table
1, indicating elevated levels of ESR, CRP, LDH, and CPK, and diminished
serum calcium (Ca corrected= 7.6), as well as negative blood and urine
culture.

Table 1

In addition to wound cleaning and debridement, the patient received the
second dose of tetanus immune globulin (500 IU), diazepam (20 mg), and
labetalol 10 mg/hr in the emergency department. The patient was isolated
in a dark, quiet room in the ICU because any sensory stimuli---including
light, touch, and loud noise---would trigger the spasms. Despite
receiving intravenous midazolam 30 mg/hr, morphine 2-3 mg/hr, MgSO4 5
cc/hr, and intravenous metronidazole, the patient experienced severe,
painful and refractory spasms permanently. Because of the insufficiency
of these medications to manage the spasms, a neuromuscular blocking
agent, atracurium 40 mg/hr, was administered as well. The spasm was
refractory to all these medications, and we had to start propofol
infusion 10cc/hr on the third day of ICU admission for 48 hours. This
regimen was followed by intravenous phenobarbital 1 gr as loading dose
and 100mg/8hr as maintenance dose. The tracheostomy was performed on the
sixth day of ICU admission. The spasm gradually decreased after
administering phenobarbital on day 10 of ICU admission; therefore,
atracurium and midazolam were gently tapered down to discontinue the
medication on day 12 and 25 of ICU admission, respectively. Finally, he
was extubated from mechanical ventilation in day 30 of ICU admission. It
is worth mentioning that the phenobarbital serum level was at the
therapeutic range (between 25-30 mg/L, therapeutic level is 10-40 mg/L
in our hospital laboratory) during the survey.

It should be noted that because of MgSO4 infusion and the patient's low
calcium level at baseline, we also administered calcium gluconate
supplement intravenously to keep his corrected calcium level above 8.5
mg/dl. Meanwhile, he received pantoprazole and heparin for stress ulcer
and DVT prophylaxis from the first day of ICU admission. On the other
hand, the patient need high energy due to continuous muscle overactivity
and spasms, but he could not tolerate enteral nutrition and had
excessive residue volume, so total parenteral nutrition (TPN) started on
day 4. The ESR, CRP, LDH, and CPK levels decreased gradually and
normalized on day 28. Finally, on day 42 of hospitalization and after
receiving the second dose of the Td vaccine, the patient was discharged
with no symptom recurrence. A written informed consent was obtained from
the patient in order to publish this case report, and it was approved by
the Research Ethics Committee of Sina Hospital.

\textbf{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.

\textbf{Conclusion}

Although there are guidelines for managing generalized tetanus, no
preferred combination therapy has been established until now. Our study
found adding phenobarbital to first-line medicine could reduce sever
spasm more quickly with no adverse reaction. However, further studies
are required to understand the best combination and dosage of
medications for severe tetanus management.

\textbf{Conflict of interests}

On behalf of all of the authors, the corresponding author declares no
conflict of interests

\textbf{Acknowledgement}

We are grateful to all the nurses and staff of the ICU of Sina Hospital
who helped us manage this case and provided valuable care.

\textbf{Funding}

The authors received no financial support for research, authorship, or
publication of the paper.

\textbf{Authorship:}

AA, HSH, AN, MM, MahM carried out diagnostic management. EK and RN
contributed in writing of manuscript and organizing patient's files. AA
revised the manuscript. All authors read and approved the final
manuscript.

\textbf{Ethics approval and consent to participate}

Written informed consent for publication of their clinical details
and/or clinical images was obtained from the patient/parent/guardian/
relative of the patient. A copy of the consent form is available for
review by the Editor of this journal.

\textbf{Data availability statement}

The data of the study are available from the corresponding author upon
rational request.

\textbf{References}

1. Shah B. A review on pharmacological management of generalised
tetanus. Gen Med (Los Angel). 2018;6(01).

2. Attygalle D, Rodrigo N. New trends in the management of tetanus.
Expert review of anti-infective therapy. 2004;2(1):73-84.

3. Hasnain MG, Maruf S, Nath P, Anuwarul A, Ahmed MNU, Chowdhury IH, et
al. Managing severe tetanus without ventilation support in a
resource-limited setting in Bangladesh. The American Journal of Tropical
Medicine and Hygiene. 2018;99(5):1234.

4. Govindaraj GM, Riyaz A. Current practice in the management of
tetanus. Critical Care. 2014;18:1-2.

5. Lisboa T, Ho Y-L, Henriques Filho GT, Brauner JS, Valiatti JLdS,
Verdeal JC, et al. Guidelines for the management of accidental tetanus
in adult patients. Revista Brasileira de Terapia Intensiva.
2011;23:394-409.

6. George EK, De Jesus O, Vivekanandan R. Clostridium tetani. StatPearls
{[}Internet{]}: StatPearls Publishing; 2021.

7. Seo SW, Lee J, Yoo B-G, Kim J, Huh S-Y. Autonomic instability in
severe tetanus: a case report. Annals of Clinical Neurophysiology.
2021;23(2):117-20.

8. Karnad DR, Gupta V. Intensive care management of severe tetanus.
Indian Journal of Critical Care Medicine: Peer-reviewed, Official
Publication of Indian Society of Critical Care Medicine. 2021;25(Suppl
2):S155.

9. Ablett J, editor Analysis and main experience in 82 patients treated
in Leeds tetanus unit. Symposium on tetanus in Great Britain, 1967;
1967: Natinal Lending Library.

10. Ingersoll K. A Review of Tetanus, Diphtheria, and Pertussis for
Pharmacists and Pharmacy Technicians.

11. Hao NV, Yen LM, Davies-Foote R, Trung TN, Duoc NVT, Trang VTN, et
al. The management of tetanus in adults in an intensive care unit in
Southern Vietnam. Wellcome Open Research. 2021;6.

12. Bleck TP. Pharmacology of tetanus. Clinical neuropharmacology.
1986;9(2):103-20.

13. Nepal G, Coghlan MA, Yadav JK, Kharel S, Ka Shing Y, Ojha R, et al.
Safety and efficacy of Magnesium Sulfate in the management of Tetanus: A
systematic review. Tropical Medicine \& International Health.
2021;26(10):1200-9.

14. Toh HC, Tiam AP. Severe tetanus in a patient with ulcerating
inflammatory breast carcinoma: A case report and review of management.
Acta Oncologica. 1997;36(1):94-6.

15. Dressnandt J, Konstanzer A, Weinzierl F, Pfab R, Klingelhöfer J.
Intrathecal baclofen in tetanus: four cases and a review of reported
cases. Intensive care medicine. 1997;23:896-902.

16. Okidi R, Sambo VDC, Eyul J. Neonatal tetanus in St. Mary's Hospital
Lacor: A case report. Clinical Case Reports. 2020;8(11):2234-6.

17. Okoromah CA, Lesi AF. Diazepam for treating tetanus. Cochrane
database of systematic reviews. 2004(1).

18. Organization WH. Current recommendations for treatment of tetanus
during humanitarian emergencies: WHO technical note. World Health
Organization; 2010.

19. Hibberd PL, Weller P, Mitty J. Tetanus-diphtheria toxoid vaccination
in adults. UpToDate, Waltham, MA. 2011.

Table 1: Patient's laboratory data at the admission and discharge from
ICU\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Parameter & ICU admission & Discharge from ICU & Normal value
\textsuperscript{a}\tabularnewline
WBC (cell/mm3) & 13100 & 6200 & 4100--10100\tabularnewline
Hgb (g/dl) & 11 & 11.2 & 12--16\tabularnewline
MCV (fl) & 88.9 & 89.6 & 77--94\tabularnewline
RBC (million/mm3) & 3.58 & 4.10 & 4.2--5.8\tabularnewline
Platelet (cell/mm3) & 322000 & 316000 & 150000--400000\tabularnewline
ALT (U/L) & 24 & 18 & \textless{} 41\tabularnewline
AST (U/L) & 36 & 28 & \textless{} 37\tabularnewline
Bilirubin Total (mg/dl) & 0.47 & 0.62 & 0.1--1.2\tabularnewline
Bilirubin Direct (mg/dl) & 0.17 & 0.22 & \textless{} 0.3\tabularnewline
ALP (U/L) & 426 & 126 & 70--306\tabularnewline
ESR (mmol/hr.) & 84 & 10 & Male\textless{}22\tabularnewline
CRP (mg/L) & 74 & 6 & Adult\textless{}6\tabularnewline
LDH (U/L) & 2518 & 120 & 350\textless{}\tabularnewline
CPK (U/L) & 10852 & 186 & Male\textless{}174\tabularnewline
PT (second) & 16.3 & 16.3 & 11-15\tabularnewline
INR & 1.3 & 1.2 & 1-1.2\tabularnewline
APTT (second) & 38.2 & 36 & 25-40\tabularnewline
Serum Cr (mg/dl) & 0.92 & 1.02 & 0.7--1.4\tabularnewline
Urea (mg/dl) & 24 & 32 & 15-50\tabularnewline
Na (meq/L) & 139 & 137 & 135-145\tabularnewline
K (meq/L) & 3.78 & 4.2 & 3.5-5\tabularnewline
Mg (mg/dl) & 3 & 2.4 & 1.6-2.6\tabularnewline
Ca (mg/dl) & 6 & 7.8 & 8.6-10.2\tabularnewline
P (mg/dl) & 2.7 & 2.2 & 2.5-5\tabularnewline
Alb (g/dl) & 2 & 2.8 & 3.5-5.5\tabularnewline
\textsuperscript{a} Normal range in our hospital's Laboratory &
\textsuperscript{a} Normal range in our hospital's Laboratory &
\textsuperscript{a} Normal range in our hospital's Laboratory &
\textsuperscript{a} Normal range in our hospital's
Laboratory\tabularnewline
\bottomrule
\end{longtable}

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