DECISION

PROMULGATING INTERIM GUIDELINES FOR DIAGNOSIS AND TREATMENT OF BOTULISM POISONING

MINISTER OF HEALTH

Pursuant to the Government’s Decree No.75/2017/ND-CP dated June 20, 2017 on functions, duties, powers and organizational structure of the Ministry of Health;  

At the request of Bach Mai Hospital in Official Dispatch No. 1059/BVBM-KHTH dated 04/9/2020 regarding formulation of guidelines for diagnosis and treatment of botulism poisoning;

At the request of the Head of the Medical Services Administration - Ministry of Health,

HEREBY DECIDES:

Article 1. Promulgated together with this Decision are the interim guidelines for diagnosis and treatment of botulism poisoning.

Article 2. These interim guidelines for diagnosis and treatment of botulism poisoning are applicable to all state-owned and private healthcare establishments across the country.

Article 3. This Decision takes effect from the date on which it is signed.

Article 4. Head of the Medical Services Administration, Chief of the Ministry Office, Chief Inspector of the Ministry of Health; heads of affiliates of the Ministry of Health; directors of hospitals and institutes with hospital beds affiliated to the Ministry of Health; directors of Departments of Health; heads of health units of other ministries and central authorities; and heads of relevant units shall implement this Decision./. 

INTERIM GUIDELINES

DIAGNOSIS AND TREATMENT OF BOTULISM POISONING
(Enclosed with Decision No. 3875/QD-BYT dated September 07, 2020 by the Minister of Health)

I. OVERVIEW

Foodborne botulism is usually caused by ingestion of food contaminated with the botulinum toxins, which are produced by Clostridium strains.

Main picture includes descending, symmetric neuropathy, paralysis of all muscles at various levels, no loss of sensory functions or awareness. Severe poisoning leads to respiratory paralysis, respiratory failure, which can be fatal. Persistent, severe paralysis results in many complications.

Poisoning does not occur frequently and may occur as one event with multiple victims. There are also individual cases with unclear epidemiological factors, rapid progression and/or lack of characteristic signs, causing the physician to overlook botulism or mistake it for another disease.

Healthcare workers need to raise their awareness, investigate the patient’s medical history and make special differential diagnosis of neuropathy to facilitate early diagnosis and treatment and administer antitoxins as soon as possible to mitigate toxic effects.

These guidelines are not applicable to wound botulism, infant botulism, adult intestinal toxemia botulism and inhalation botulism.

2. CAUSES

a) Toxin-producing bacteria

- Clostridium bacteria producing the botulinum toxins are divided into the following 4 strains:

+ (1) Clostridium botulinum, which produce botulinum toxins of types A, B, C, D, E, F and G.

+ (2) C. baratii, which produce botulinum toxins of type F.

+ (3) C. butyricum, which produce botulinum toxins of type E.

+ (4) C. argentinense, which produce botulinum toxins of type G.

- These are Gram-positive, rod-shaped, anaerobic, spore-forming bacteria. Their spores are found in the earth, air, seawater and seafood intestine, and can survive at 100°C and 1 atm pressure for several hours.

b) Toxins

- Only botulinum exotoxins of types A, B, E and F cause human botulism. Botulinum toxin is a protein of approximately 150 thousand Dalton that is easily destroyed by boiling (poisoning can be prevented by eating cooked food).

- A patient can be poisoned by one or more than one type of toxin.

c) Sources of foodborne botulism

- The original source is canned meat. However, botulism cases around the world show that botulinum spores can grow into bacteria and excrete exotoxins in all vegetables, meat, seafood, etc. that are improperly produced and kept in unsafe tightly sealed containers (e.g., cans, bottles, jars, bags).

- One common source includes food that is processed and packaged manually, on a small scale or in unqualified production establishments. The bacteria can also be found in manufactured food and food in restaurants.

- Foodborne botulism is on the rise around the globe due to the vacuum packing trend, unsafe food preservation, improper refrigeration use and lack of pre-consumption boiling.

- In special cases, botulinum toxins can be added to food for terrorism purpose.

d) Toxicokinetics and toxicology

- Botulinum toxins are not destroyed by gastric acid and digestive enzymes, and mainly absorbed from the duodenum and jejunum into the blood. Their target organs are the cholinergic synapses in the peripheral nervous system, parasympathetic nerve endings and glands, and inside nerve cells. Absorption, metabolism and elimination of these toxins are unclear.

- Mechanism of action: botulinum binds to the presynaptic axon terminal irreversibly, cutting important protein structures at the axon terminal membrane and membranes of acetylcholine vesicles, preventing the release of acetylcholine into the synaptic cleft and in parasympathetic and cholinergic postganglionic sympathetic neurons. The affected synapses might need to regrow their axons and form new synapses to recover. The central nervous system and sensory nervous system are unaffected.

- Lethal dose: a 0,09 mcg intravenous injection can kill a 70kg person.

3. DIAGNOSIS

3.1. Diagnosis

a) Food causing suspicion: the abovementioned types of food, uncooked food or cooked food left for long.

b) Epidemiological factors: at least 2 persons developing the same manifestation(s) after consuming the same food. There might be individual cases occurring at different locations.

c) Onset: usually 12-36 hours after food consumption, mostly in the first day, approximately 6 hours to 8 days after food consumption.

d) Clinical

* Vital signs: no fever (unless due to other causes), blood pressure might drop while heart rate tends to not increase.

* Gastrointestinal symptoms: nausea, vomiting, abdominal distension and/or stomach cramps develop early, before paralytic ileus, constipation.

* Neurological symptoms:

- Symmetric paralysis, starting from the head and neck to the legs: from the cranial nerves (ptosis, diplopia, blurred vision, throat pain, speaking difficulty, swallowing difficulty, hoarse voice, dry mouth), And then arm paralysis, paralysis of chest and abdominal muscles and leg paralysis.

- Decrease in or loss of stretch reflexes.

- Lucidity.

- Possible dilation of both pupils.

- No sensory disturbances.

- Paralysis level: from mild (fatigue, muscle fatigue similar to asthenia, inability to perform normal effortful tasks)  to severe (sputum build-up, haemoptysis, easily choking, respiratory failure). The patient may develop paralysis of all muscles and dilation of both pupils and require breathing support, which can be mistaken for coma or vegetative state (the patient is actually awake unless there is lack of oxygen to the brain).

- Average duration of mechanical ventilation prior to ventilator withdrawal is 2 months for patients poisoned with type A toxin and 1 month for those with type B toxin. However, patients might need up to 100 days before they start recovering.

- Atypical picture (accounting for 7%): hemiparesis or ascending paralysis.

*Respiratory symptoms: possible respiratory failure, sputum build-up, haemoptysis, breathing difficulty, rapid shallow breathing due to paralysis of the intercostal muscles, diaphragm.

* Urology symptoms: urinary retention, distended bladder

e) Paraclinical

* Regular laboratory and functional tests:

- Blood tests: complete blood count, urea, sugar, creatinine, bilirubin, electrolyte panel (Na, K, Cl, Ca), GOT, GPT, CPK.

- Arterial blood gas to assess respiratory failure.

- Urine: protein, erythrocyte, leukocyte.

- ECG.

- Lung X-rays.

- Laboratory and functional tests for differential diagnosis: brain CT scans, cranial MRI scans, cerebrospinal fluid analysis, etc.

* Electrophysiology study: performed upon appearance of muscle weakness or paralysis for clinical diagnosis, even when it is late.

- Normal sensory nerve action potential.

- Stark decline in electric potential but nerve conduction velocity remains unaffected.

- High frequency repetitive nerve stimulation leads to limited increase in evoked electric potential amplitudes (high increase is present in Lambert-Eaton syndrome; decrease in amplitudes upon low frequency repetitive nerve stimulation is present in myasthenia gravis).

- Electromyography: characteristic signs include decrease in amplitudes and shortening of the duration of action potential in motor units due to blockade of intrafusal muscle fibres. There is also the multi-phase phenomenon in action potential in motor units.

- Spontaneous activities, positive sharp waves or fibrillation potentials are usually present.

- In botulism, there is no increase in evoked electric potential amplitudes upon repetitive stimulation of small muscle groups with increasing frequency.

* Tests for bacteria and toxins

+ Support diagnosis and determination of cause of poisoning. If certain about clinical diagnosis, administer antitoxins without waiting for positive test results. These tests are usually conducted in advanced laboratories such as those in institutes of hygiene and epidemiology and institutes of drug quality control.

+ In case a sample cannot be sent yet, collect, retain and send it to a qualified laboratory.

+ Samples include samples of the food causing suspicion, vomit, gastric lavage, intestinal fluids (if the patient has just consumed food; intestinal fluids shall be obtained via autopsy), stool (the bacteria are still present when the patient arrives late), isolated colonies of Clostridium strains. Patients usually experience constipation and might require laxatives or enema to obtain their stool.

+ Ensure safety when coming into contact with samples: as the botulinum toxin is highly poisonous, ensure safety when collecting, retaining, transporting and handling samples. The samples need to be kept in the refrigerator.

- Culture to identify the disease-causing Clostridium strain: anaerobic culture.

- Botulinum toxin detection:

+ Notes for blood samples:

√ As the toxin concentration is low, perform confirmatory testing early, highest chance of positive test result is within 1-2 days after consumption of contaminated food. Toxin survival time: for type A toxin, after absorbed into the bloodstream, it will quickly move to target destinations, leading to high chance of negative test result; for types B and E toxins, if antitoxin is not administered, they can survive in the bloodstream for 10-20 days after food consumption.

√ Collect and keep 10ml of blood prior to antitoxin administration (the antitoxin will neutralize free toxin) and prior to edrophonium injection (if planning to perform a Tensilon test, as edrophonium or drugs in the same class can be toxic to mice when testing the toxin on mice).

+ Toxin detection methods: choose from the following methods depending on each laboratory’s capacity:

√ Mass spectrometry (yield result within a day).

√ Testing on mice (using serum sample, sensitive, can detect toxin with a concentration of 5-10 pg/ml, yield result in 3-5 days).

√ Pulsed-field gel electrophoresis in combination with randomly amplified polymorphic DNA analysis.

√ ELISA test.

* Make a diagnosis based on:

- Typical clinical picture after eliminating other diseases (see differential diagnosis), or:

- Clinical picture in combination with positive test result for botulinum toxin or C. botulinum, C. baratii, C. butyricum, or C. Argentinense bacteria in a sample (food causing suspicion, vomit, gastric lavage, intestinal fluids, feces, blood), or:

- Typical clinical picture and epidemiological relevance to a confirmed case of foodborne botulism.

3.2. Differential diagnosis:

Below is a table presenting differential diagnosis of foodborne botulism and other diseases.

Table 1: Differential diagnosis of foodborne botulism and other diseases

4. HANDLING

4.1. Rules

- Provide emergency aid and CPR are the main handling measures: detect respiratory paralysis early on, manage the airway, put the patient on breathing support and detect accompanying respiratory problems.

- Administer the specific antitoxin as soon as possible upon indication.

- Report to regulatory bodies for cooperation in handling.

4.2. Specific measures

4.2.1. Patient receipt

a) Clear poisoning symptoms (clear muscle weakness, paralysis), regardless of the food source and time of consumption: admit the patient.

b) When the source of poisoning has been identified

* More than 8 days have passed since the last time the patient consumes the food

- The patient shows no symptoms: they are not poisoned.

- The patient develops mild symptoms (fatigue, asthenia): hospitalize the patient if the symptoms worsen; if the patient’s condition is stable or is gradually improving, release the patient into the care of grassroots health units after a full assessment.

* Within 8 days after the last time the patient consumes the food: admit the patient for assessment and monitoring if they develop symptoms. Allow the patient to go home and prescribe activated charcoal and laxatives for them if they have no symptoms, provide instructions on monitoring at home and visiting the nearest healthcare establishment for examination (after a full assessment).

4.2.2. Detoxification

- Induce vomiting: if the patient has just consumed the food causing suspicion.

- Administer activated charcoal: most patients arrive at the hospital late, however, activated charcoal is recommended as the toxins as well as the bacteria can survive in the gastrointestinal tract for many hours to many days later. Administer a dose of 1g/kg in combination with a dose of sorbitol equivalent to that of activated charcoal used.

4.2.3. Symptom treatment

The patient requires close monitoring, especially paralysis and respiratory monitoring.

a) Respiratory failure: handle according to severity

- Pharyngeal paralysis, haemoptysis, sputum build-up: collect sputum, let patient lie on their side and feed via a feeding tube. Intubate the patient early on to protect their airway.

- Respiratory failure: intubate the patient and put them on a ventilator.

- Resuscitate and put the patient on a ventilator similar to how patients with a neuromuscular disease are handled.

- Make preparation for long-term ventilation.

b) Gastrointestinal symptoms

- The patient usually experiences decrease in bowel movements, paralytic ileus while botulinum spores are present in the gastrointestinal tract.

- Closely monitor the patient’s bowel movements, digestion, defecation and blood potassium.

- Increase blood potassium in case of low blood potassium.

- Metoclopramide:

+ Adults: 10mg/time, 3 times/day, intravenous injection.

+ Children: 0,1mg/kg/time, 3 times/day, intravenous injection.

- Constipation treatment: can use sorbitol: 1g/kg, oral administration, discontinue if diarrhea occurs.

- For pediatric and elderly patients consuming food contaminated with the toxin while using antibiotics (risk of spores growing in the gastrointestinal tract): should administer digestive enzymes.

- Diet: increase fiber.

- Bowel movement stimulation measures: increase passive exercise, physical therapy, abdominal massaging.

c) Complication prevention and treatment

- Hospital-acquired infection

- Prevent ulcers, maintain patient’s personal hygiene

4.2.4. Antitoxins

- Botulinum antitoxin is comprised of antibody/neutralizing antibody fragments capable of neutralizing the botulinum toxin. The antitoxin must contain all antibodies/neutralizing antibodies against each toxin component that is poisonous to humans. In theory, the antitoxin is only effective against free toxins and not toxins bound to nerves, thus, it cannot immediately reverse paralysis. However, the antitoxin can prevent the poisoning from worsening and shorten the poisoning duration, ventilation duration, recovery time and hospitalization time significantly.

- The antitoxin is an orphan drug and its preparations are available in limited quantity under orphan drug programs of other countries. One preparation frequently mentioned in recent documents and currently prioritized is Botulism Antitoxin Heptavalent (made from horses, containing F(ab')2 antibody fragments effective against botulinum toxins of types A, B, C, D, E, F, and G).

a) Indication

- The antitoxin is indicated for foodborne botulism with clear symptoms and should be given as soon as possible, preferably before the symptoms worsen; however, the antitoxin can be indicated for any stage of poisoning during which the patient is in serious condition.

- Administer the antitoxin without waiting for toxin testing or culturing results.

b) Caution: especially for those allergic to equine biologicals (obtain patient’s allergy history). Persons with allergies (asthma, past allergies, hives, prurigo, dermatitis, allergic rhinitis).

c) Dose and use

- Can give corticosteroid first to prevent allergic reactions.

- Persons of at least 17 years of age: 1 vial, regardless of the patient’s weight, dilute with 0,9% sodium chloride at a ratio of 1:10, administer via the intravenous route: initial velocity at 0,5ml/minute, double the velocity every 30 minutes if nothing is amiss but keep the velocity under 2ml/minute.

- Persons from 1 to 16 years of age: calculate the dose based on the patient's weight and as a percentage of the adult dose (1 vial). Dilute the whole vial as abovementioned, and then give a dose calculated based on the patient’s weight. Specific dosage is provided for in the following table:

Table 2. Pediatric dosage of Botulism Antitoxin Heptavalent

- Children under 1 year of age: 10% of adult dose, equivalent to 10% of 1 vial. Dilute as abovementioned, initial IV velocity at 0,01ml/kg/minute, increase by 0,01ml/kg/minute every 30 minutes if nothing is amiss, keep maximum velocity at 0,03ml/kg/minute.

4.2.5. Cooperation with regulatory bodies

Notify regulatory bodies immediately (preventive medicine authorities, food safety authorities, local health authorities, etc.) upon receipt of a patient suspected of foodborne botulism.

5. PROGNOSIS AND COMPLICATIONS

a) Prognosis

Foodborne botulism is a serious and highly fatal type of poisoning with prolonged paralysis. Average duration of mechanical ventilation prior to ventilator withdrawal is 2 months; however, patients require months to recover.

b) Complications: main complications:

- Hospital-acquired infection, especially pneumonia and ventilator-associated complications.

- Complications arising from prolonged immobilization and bed rest, ulcers.

- Paralytic ileus, constipation, gastroesophageal reflux disease, pulmonary aspiration.

6. PREVENTION

- For regulatory bodies: increase food safety inspection.

- For people:

+ Choose products from reliable sources and of recognized quality and safety.

+ Be careful with food packaged in the abovementioned forms that has an abnormal smell, color or taste (e.g., yogurt that does not taste as sour as it is supposed to).

+ Avoid self-packaging food and keeping food for a long time using a non-freezing method (only freezing can stop bacterial growth and toxin production).

+ Prioritize recently processed and cooked food. Note that proper cooking can destroy the botulinum toxin (if it is unfortunately present in the food).

+ For traditionally packaged or fermented food (such as pickled vegetables): ensure that the food is sour and salty. Do not eat food that is no longer sour.

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