The management of tetanus in adults in an intensive care unit in Southern Vietnam

Background: Tetanus remains common in many low- and middle-income countries (LMICs) yet the evidence base guiding management of this disease is extremely limited, particularly with respect to contemporary management options. Sharing knowledge about practice may facilitate improvement in outcomes elsewhere. Methods: We describe clinical interventions and outcomes of 180 adult patients ≥16 years-old with tetanus enrolled in prospective observational studies at a specialist infectious diseases hospital in Southern Vietnam. Patients were treated according to a holistic management protocol encompassing wound-care, antitoxin, antibiotics, symptom control, airway management, nutrition and de-escalation criteria. Results: Mortality rate in our cohort was 2.8%, with 90 (50%) patients requiring mechanical ventilation for a median 16 [IQR 12-24] days. Median [IQR] duration of ICU stay was 15 [8-23] days. Autonomic nervous system dysfunction occurred in 45 (25%) patients. Hospital acquired infections occurred in 77 (43%) of patients. Conclusion: We report favourable outcomes for patients with tetanus in a single centre LMIC ICU, treated according to a holistic protocol. Nevertheless, many patients required prolonged intensive care support and hospital acquired infections were common.


Introduction
Tetanus is a vaccine-preventable disease that remains a common cause of acute critical illness in low-income and middle-income countries (LMICs) 1 . Signs and symptoms are due to the effects of tetanus toxin in the central nervous system and management is based on three key strategies: blocking further tetanus toxin release 2 , neutralising unbound toxin 3 , and alleviating effects of already-bound toxin; namely muscle spasms and autonomic nervous system dysfunction 1,4,5 . With access to critical care interventions such as mechanical ventilation and advanced physiological monitoring, muscle spasms and autonomic nervous system dysfunction (ANSD) can be more easily managed 6-8 . These interventions are now available in many LMIC intensive care units (ICUs); however, their availability is often not associated with improved outcomes 9,10 .
As almost all tetanus occurs in settings with limited capacity for clinical trials, the evidence base for tetanus management remains limited. There are few randomized clinical trials to support common management strategies and, in the absence of high-quality evidence, observational studies and case series become the key elements in guiding treatment. The Hospital for Tropical Diseases, Ho Chi Minh City, has been a tertiary referral centre for tetanus for over 30 years and has developed and implemented a specific holistic management protocol for patients with tetanus. The ICU continues to admit several hundred adult patients with tetanus every year and reports outcomes comparable with those from high income settings 7,11 .
The overall aim of this paper is to pragmatically describe the intensive care management of adult tetanus in a LMIC setting but nevertheless one with amongst the lowest reported case fatality rate worldwide 12 .

Setting
The Hospital for Tropical Diseases (HTD), Ho Chi Minh City is a tertiary referral centre for infectious diseases serving Southern Vietnam. Previously the hospital housed a special tetanus ICU but whilst this no longer exists, the hospital's adult ICU continues to receive 250-350 adult patients with tetanus annually. The principles of tetanus management described above have been incorporated into a specific treatment protocol (Figure 1), which has been applied consistently to all patients over a 10 year period 12 . In addition to pharmacological interventions, the protocol includes directions for airway management, nutrition and nursing observations. It also includes criteria for de-escalation and discharge from hospital.
Participants and data collection Data on management and outcome of patients treated with this protocol were collected from two prospective observational studies, recruiting two cohorts of patients ≥16 years old admitted to the hospital's ICU with a diagnosis of generalized tetanus; the first from August 2016 -March 2017 and the second from January -July 2018. For patients enrolled between August 2016 and March 2017, additional exclusion criteria were: (i) not speaking Vietnamese, (ii) not being able to walk before admission.
Baseline and clinical variables including patient demographic details, tetanus severity indicators and management interventions and complications were collected prospectively on all enrolled subjects. Enrolled patients were followed daily until hospital discharge. Previously described definitions were applied for hospital acquired infections 13 . Autonomic nervous system dysfunction (ANSD) was defined as at least three of: heart rate >100 beats per minute (bpm), systolic blood pressure >140 mmHg, mean arterial pressure < 60 mmHg, pyrexia > 38°C, and fluctuating blood pressure. All features should be present within one day with no other apparent cause 14 . Sensitivity evaluation of mortality rates within this study was performed by comparing with overall hospital database for outcomes of all patients with tetanus (ICD10 code A35) during the period 2016-2018.

Statistical analysis
Descriptive statistics were used to describe the sample with the median and interquartile range (IQR) for continuous data, and count and percentage for categorical data. Due to small numbers of those who died, no comparative statistics have been performed. All analyses were carried out in Stata (StataCorp) version 16. Missing data are included and described in tables.

Ethics statement
This study was approved by the London School of Hygiene and Tropical Medicine (LSHTM) ethics committee, the Oxford Tropical Medicine Ethics Committee (OxTREC) and the local HTD ethics committee (Refs 16904, 596-16, 816 QD-BVBND, 38-17, 494/ QD -SYT respectively.) All participants gave written informed consent to participate before enrolment.

Results
In total, 180 patients with generalised tetanus admitted to the ICU at HTD between August 2016 and July 2018 were included in this study. During the first period, 80 out of a total 160 admissions 80 patients were enrolled. For the second period, 100 patients were included out of a total of 120 admissions during that time. Reasons for lower enrolment of the first cohort were largely pragmatic due to lack of availability

Amendments from Version 1
The revised document includes some clarifications and additions in response to the reviewers' comments. Principally these are some clarification in the methods section why the two cohorts of patient data were collected from different periods and with some differences in entry criteria for the original studies. Secondly, a new table (Table 3) has been added to show data about cause of death rather than in text. As numbers are very small, no comparative hypothesis testing was performed and the table contains descriptive data only. A paragraph has been included in the discussion to include a limitation in that the protocol did not include rehabilitation.

REVISED
of study staff and more stringent enrolment criteria. The median [IQR] age of the patients was 51.0 [40.8-61.5]. The youngest age was 17 and the oldest 98 years old. Of 180 patients, 73 (40.6%) had at least one comorbidity and 143/180 (79.4%) were male. Median Tetanus Severity Score on admission was 1.5 [IQR -3 -5], with median time from first symptom to admission of 3 [IQR 2-5] days 15 . Severe tetanus, defined as Ablett grade 3 or 4 on hospital admission (i.e. spasms interfering with respiration with/without autonomic nervous system dysfunction), was diagnosed in 28 patients (16%), but an additional 66 (37%) progressed to severe disease during hospitalization ( Table 2).
A summary of the management and complications of the patients during ICU admission are described in Table 1 and  Table 2.
Description of the cases who died Of the 5/180 (2.8%) patients that died, 3 deaths were caused by cardiogenic shock (occurring at days 2, 12 and 15 of ICU  admission), one death was due to septic shock secondary to ventilator associated pneumonia (occurring at day 5 of ICU admission) and one was due to ischaemic bowel and perforation (occurring at day 28 of ICU admission). A comparison of clinical features with those who survived is given in Table 3.
Review of hospital records showed that in total, during the three years 2016-2018, 917 adults were admitted with tetanus with an overall case fatality rate of 4% (including palliative discharges).

Discussion
We describe clinical features and outcomes of a large cohort of patients with tetanus managed at a specialist tetanus centre. Patients were managed in accordance with a standardized protocol by a team of doctors and nurses with significant experience in tetanus management 7 .
The case fatality rate in this study is 2.8%. This is, to our knowledge, the lowest reported mortality rate for a large series of tetanus patients worldwide 12 , and contrasts with rates reported from many other LMICs where rates of 45 to 58% have been reported despite the availability of mechanical ventilation 10,16,17 . Whilst it is possible that selection bias has influenced our results, our figures are similar to official hospital records over the study period as well as an observational study enrolling patients with severe tetanus from our centre and one other major centre in Vietnam between 2013 and 2015 18 . We have previously reported a fall in mortality from 28% to 8% between 1994 and 2001 as more comprehensive ICU facilities became available 20 . Comparison with contemporary data from other countries is more difficult due to limited reporting of established tetanus severity scores or known prognostic features. Nevertheless, the age of patients in our study (one of the strongest predictors of outcome) is similar to, or even older than, those reported in other centres with worse outcomes 10,21,22 . Similarly, our ventilation rate was 50% but rates between 50% and 75% elsewhere have been associated with mortality rates of 30-35% 10,22,23 . We report a relatively high rate of hospital acquired infection in this cohort, which is similar to those previously observed in patients with tetanus. Previous work has indicated that these infections are related to length of ICU stay, however compared to patients with other diseases, those outcomes in patients with tetanus and hospital acquired infections are favourable 18 We believe that the favourable outcomes at our centre result from two major factors: a clear management protocol and care by a highly specialized team with enormous experience in tetanus. Throughout the world, protocolized medical care is encouraged as a means of improving patient outcomes. Ideally, protocols are based on best evidence and can be regularly updated. However, this is not the case for many of the elements of our protocol due to the lack of high-quality contemporary evidence for tetanus management. Nevertheless, the outcomes in our patients to some extent supports their continued use. A limitation of our work is that protocol adherence itself was not specifically measured. Personal experience and treatment intervention data reported herein indicate that adherence was high; however, we have not specifically examined compliance with individual components of the protocol.
Our hospital is a tertiary infectious disease centre and receives patients with tetanus from Southern Vietnam. A highly developed referral system and limited staff turnover within the ICU means that experience in management of tetanus can be more readily easily developed and preserved. Tetanus is a disease where progression continues to occur after hospitalization. Experienced staff may therefore be better able to anticipate complications, and so arrange care and interventions more appropriately. They may also be able to pass on subtle elements of care not outlined in our protocol -for example exactly when to intervene with spasms or how to balance risk of pressure area necrosis and spasm provocation when turning a patient. Finally, as a tertiary infectious disease centre there may be further factors that particularly benefited outcomes, such as more careful prevention or management of hospital acquired infections which are particularly frequent in severe tetanus.
Sharing these forms of tacit knowledge is a challenge for health systems across the world but is most likely to benefit lower resourced settings with less access to specialised training and referral. The current expansion of digital technologies may offer possible solutions. For example, newer technologies in the form of telemedicine or even AI-enabled risk stratification may facilitate dissemination of less explicit knowledge or even simplify analysis of these complex processes.
Additionally, our protocol does not include recommendations for physical rehabilitation, although we have previously identified a cohort of patients with reduced functional outcome after hospital discharge 20 . Understanding what is the most appropriate rehabilitation strategy for our context and which patients would benefit from this, is a research priority if long-term outcomes are to be maximized.

Conclusions
We report management and outcome features in a large contemporary cohort of patients with tetanus treated according to a standardized protocol. Survival rates of these patients are high compared to other reported case series. Nevertheless, other outcomes such as duration of hospitalization and mechanical ventilation requirements indicate that tetanus remains a significant burden on healthcare services. Therapies that can reduce these continue to be needed.
This project contains the following underlying data: -ORA_04TSSF36.xlsx (This is a data set from a clinical observation study. The data was manually entered from case record forms to a specific database. This dataset is from the exported data. Favorable outcomes of adult patients with generalized tetanus are attributed to consistent, holistic, evidence-based and protocolized management by a highly experienced team at a specialist infectious diseases hospital in Southern Vietnam that receives 250-350 adult patients annually. This prospective observational study describes the pragmatic management and outcomes of 180 patients in two cohorts (August 2016 -March 2017 and January -July 2018) that were followed daily till hospital discharge. Factors like age, need for mechanical ventilation (50%), autonomic nervous system dysfunction (25%), hospital acquired infections (43%) and median length of ICU stay (15 [8-23] days) is comparable to reports from other LMICs but outcome is significantly better (2.8% vs. 44% from a Brazilian ICU).

Study Design:
The prospective observational study design describes better outcomes of adult patients admitted with generalized tetanus based on a high volume of cases referred to this tertiary center and more than 10 years experience of the team rather than adherence to the elements of the management protocol. Randomization of patients to either receive a bundled care or usual care or studying outcomes based on adherence to the holistic protocol will improve the quality of evidence generated.

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The full exclusion criteria are not mentioned. It is not clear why ALL patients admitted during the two study periods were not included in the study and 80 patients (out of 160) in the first study period and 20 (patients (out of 120) in the second study period were excluded.

Reproducibility:
To allow others to benefit from their holistic protocols more details of various elements of the protocol are needed like recommended timings of antitoxins, antibiotics, tracheostomy or mechanical ventilation, details of wound management, targets of nutrition therapy, ○ infection prevention and control protocols, routine prophylactic therapies and rehabilitation protocols, etc.
No these are not currently used.
The section on 'description of cases who died': I agree that numbers are small, but the authors could provide the information given in this section as a table comparing 'dead' vs 'survivors'-they don't have to perform any hypothesis testing.
This has been done and a table added. This was not clear -80/160 admissions during the first period were enrolled in this study and 100/120 admissions during the second period were enrolled. The text has been changed.
Line 6: why 100 patients included out of 120-reasons for exclusion of 20?
As above. Entry criteria are given in the methods.

Under 'participants and data collection': what is the justification of the additional exclusion criteria (lines 7,8)? Is it just a carryover of the exclusion criteria of the original cohort?
Yes -text has been altered.
Under 'Discussion': Para 3-the authors say their protocol is 'evidence-based' but then go on to also say that most elements don't have much evidence. I know what they mean-but they could reframe these sentences.
Thank you -we have removed these/ changed to 'best-available evidence' The authors note that for a period these patients were managed in a 'special tetanus ICU'-are there outcomes from that period? and if yes how do they compare to the later period?
Yes, we have data -added in the discussion section and cited.
I note their protocol includes elements around nutrition, discharge criteria, etc. Do they also have a plan for physiotherapy or rehab (in the later phases of illness)-these patients require prolonged periods of sedation/paralysis -hence the question.
Currently, these are not written in the protocol but we are aiming to develop these. This has been added to the discussion in the 'priorities' and future section.
I would like to understand the hospital acquired infection rate in context -how does this compare to other conditions on that specific ICU and also compared to other tetanus cohorts (43% is high).
In this study, we have not specifically looked at that, however previous studies have examined this. We have included a discussion around this in the discussion section.
Essentially what we have found in previous studies is that although rates are high, this is generally due to the length of ICU stay and that outcomes are actually relatively good.
In the discussion, please can you add the case fatality rates from other settings for direct comparison (e.g. https://pubmed.ncbi.nlm.nih.gov/33824951/)1.
These have been added and the citation above also included.

Competing Interests:
No competing interests were disclosed.