Intrathecal Tetanus Immunoglobulin to Treat Tetanus

Study Overview
=================
Brief Summary
-----------------
To establish whether the addition of intrathecal tetanus antitoxin reduces the need for mechanical ventilation in patients with tetanus

Detailed Description
-----------------
The investigators will conduct a randomised partially-blinded controlled 2x2 factorial trial. First, adults admitted to the Intensive Care Unit at the Hospital for Tropical Diseases Ho Chi Minh City will be randomized to receive either human (3000 IU) or equine (21,000 units) intramuscular antitoxin. Second, participants will be randomized to receive either standard treatment with intramuscular antitoxin alone or with the addition of 500 IU intrathecal human antitoxin. Patients with prior antitoxin treatment and those with contra-indications to lumbar puncture or antitoxin treatment will be excluded. All patients will receive other standard tetanus treatment as deemed necessary by the attending physicians. Spasms will be treated with benzodiazepines as first-line therapy. Patients with spasms not controlled with benzodiazepines will receive tracheostomy, paralysis, magnesium sulphate and mechanical ventilation. Heart rate, BP, temperature and daily drug use will be recorded throughout the ICU stay. Patients will be followed following discharge from hospital until 240 days for disability/ death.

Official Title
-----------------
Intrathecal Immunoglobulin for Treatment of Adult Patients With Tetanus: a Randomized Controlled 2x2 Factorial Trial

Conditions
-----------------
Tetanus

Intervention / Treatment
-----------------
* Procedure: Human tetanus immunoglobulin
* Procedure: Intramuscular antitoxin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All adult patients (≥16 years old) with a clinical diagnosis of generalized tetanus admitted to the intensive care unit (ICU) at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam Exclusion Criteria: Prior administration of antitoxin during this episode Contra-indication to use of human or equine antitoxin Contra-indication to lumbar puncture Already receiving mechanical ventilation or expected to require this before intrathecal injection can be given Pregnancy Informed consent not obtained

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Human tetanus immunoglobulin<br>Human tetanus immunoglobulin (Tetagam-P): Injection (prefilled syringe) 250 IU in 1 ml - Intrathecal 500 IU | Procedure: Human tetanus immunoglobulin<br>* Adults admitted to ICU at Hospital for Tropical Diseases will be randomized to receive either human (3000 IU) or equine (21,000 units) intramuscular antitoxin. Second, participants will be randomized to receive the addition of 500 IU intrathecal human antitoxin.<br>* Other names: Human tetanus immunoglobulin (Tetagam-P);|
| Sham Comparator: Intramuscular antitoxin<br>Human tetanus immunoglobulin (Tetagam-P): Injection (prefilled syringe) 250 IU in 1 ml - Intramuscular 3000 IU OR Equine antiserum - 21,000 units | Procedure: Human tetanus immunoglobulin<br>* Adults admitted to ICU at Hospital for Tropical Diseases will be randomized to receive either human (3000 IU) or equine (21,000 units) intramuscular antitoxin. Second, participants will be randomized to receive the addition of 500 IU intrathecal human antitoxin.<br>* Other names: Human tetanus immunoglobulin (Tetagam-P);Procedure: Intramuscular antitoxin<br>* First, adults admitted to ICU at Hospital for Tropical Diseases will be randomized to receive either human (3000 IU) or equine (21,000 units) intramuscular antitoxin including a 0.05ml test dose (ie 75 units equine antitoxin or 12.5 IU human antitoxin). Second, participants will be randomized with sham procedure<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Requirement for mechanical ventilation during ICU stay | Criteria for mechanical ventilation are oxygen saturation (SpO2) <90%; or partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) <250; or excessive spasms necessitating muscle paralysis. These criteria are intended as a guide and the final decision to ventilate a patient rests with the individual doctor responsible for the patient. | During ICU stay, an average of 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of ICU stay |  | During ICU stay, an average of 3 weeks | 
| Duration of hospital stay |  | During hospital stay, an average of 5 weeks | 
| Duration of mechanical ventilation |  | During hospital stay, an average of 5 weeks | 
| In hospital and 240 day mortality |  | 240 days | 
| In hospital and 240 day disability |  | 240 days | 
| New antibiotic prescription during ICU stay | New antibiotic prescription during ICU stay (excluding antibiotics for tetanus or initial entry site infection) | During ICU stay, an average of 3 weeks | 
| Incidence of Ventilator Associated Pneumonia | Definition of Ventilator associated pneumonia (VAP): Mechanical ventilation for at least 48 hours and with the tube in place within the last 48 hours and 2 of: Temperature > 38°C or < 36°C White blood cell count <4.0 x 109/L or ≥12 x 109/L Purulent respiratory secretions New or progressive changes on chest radiography (for VAP) Plus for microbiologically confirmed VAP Bacterial growth of ≥105 cfu/ml from endotracheal aspirate (ETA) (or ≥104 cfu/ml from Broncho Alveolar Lavage (BAL)) | During hospital stay, an average of 5 weeks | 
| Incidence of clinical syndrome of autonomic nervous system dysfunction | At least 3 of the following criteria: Tachycardia Heart Rate (HR)> 100 bpm Hypertension Systolic Blood Pressure (SBP) > 140 mmHg Hypotension Mean Arterial Pressure (MAP) < 60 mmHg Pyrexia > 38°C Alteration between hypertension and hypotension | 240 days | 
| Total dose of benzodiazepines and pipecuronium during hospital stay |  | During hospital stay, an average of 5 weeks | 
| Incidence of adverse events |  | During hospital stay, an average of 5 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tetanus