4. Understand the pathophysiology and management of Tetrodotoxin (TTX)

KEY LEARNING OBJECTIVES 1. Describe the mechanism of action of the tetrodotoxin at a cellular level 2. Describe the pathophysiology of tetrodotoxin toxicity 3. Have a sound knowledge of clinical signs and diagnosis 4. To be able to describe and recommend a treatment plan for tetrodotoxin toxicity

TTX poisoning can occur from ingestion of a wide range of bony fish from families in the order Tetraodontiformes, most importantly the family Tetraodontidae (puffer fish, also known as toadfish).

TTX is produced by commensal bacteria which reside within the gastrointestinal tract. The toxin is then transferred into the liver, gonads and skin of the fish where it resides. It has been identified with the following species. Blue-ringed octopus, starfish, parrotfish, rough skinned newts, toads of the genus Atelopus, the angelfish, and xanthid crabs

• Tetrodotoxin (TTX) is present in high concentrations in the liver of puffer fish, with progressively decreasing amounts in the ovaries, intestines and skin. Usually the flesh or the meat of the fish is not toxic, provided it was not contaminated with the toxin from its own organs • Concentrations of TTX in the fish vary seasonally. As there is a distinct relationship between gonadal activity and toxicity, the fishes are most dangerous to eat immediately prior to and during their reproductive season • Potency is not reduced if the fish is dead or desiccated

There are approximately 30 species of Puffer fish in Australia • The common toadfish is a sandy to whitish colour, with small brown spots over most of the back and upper sides. The lower sides often have brown bars and blotches • It occurs from southern New South Wales to northern Queensland in shallow coastal waters and estuaries • The smooth toadfish looks like the common toadfish, but has larger spots and distinct body spines • With other species of puffer fish found in tropical waters, the potential for TTX poisoning exists in many coastal regions of Australia

Puffer fish are very common around jetties and shallow salt water, mudflats and estuaries. Often end up readily accessible to pets on shores, rocks and jetties after being easily caught, killed and thrown away by fisherman

Pathophysiology • TTX is a potent neurotoxin • TTX is rapidly absorbed even through mucus membranes of the mouth • TTX blocks sodium channels thus preventing the generation of action potentials • Peripheral nerve fibres are mainly affected, but autonomic nerves, sensory nerves, skeletal muscles and least commonly cardiac muscle can also be affected • This results in generalised LMN paralysis, hypoventilation or respiratory arrest, vasodilation and hypotension • Stimulation of the chemoreceptor trigger zone causes vomiting • Tetrodotoxin is a heat-stable (except in alkaline environments) and water-soluble nonprotein

Clinical Signs • Clinical signs may occur within 10 minutes, but is more common after several hours. • Death can occur as rapidly as 17 minutes • Dogs rarely show the more advanced signs as they usually vomit early before any significant absorption of toxin • Cats are more sensitive to the toxin and often don’t receive veterinary attention until death is imminent

Gastrointestinal • Vomiting • Excessive salivation

Neurological • Flaccid paralysis • Ataxia • Weakness • Difficulty to absent swallowing • Mydriasis • Slow to absent pupillary light reflex • Hypothermia

Respiratory • Dyspnoea • Tachypnoea • Hypoxia, cyanosis • Respiratory depression • Apnoea

Cardiovascular • Tachycardia or bradycardia • Hypotension • Arrhythmias • In humans, cardiovascular effects, occur only in the most severe (Grade 4) cases • Death typically from respiratory paralysis

Diagnosis • Known exposure • Foul smelling gastric contents, fishy breath • Exclude snake envenomation, and ixodes holocyclus • Rapid onset LMN clinical signs • No diagnostic tests for TTX exposure are available in the acute clinical situation

Treatment ABCDs

Decontamination • Do not induce emesis if clinical signs are present • Activated charcoal o Unlikely to absorb sufficient remaining toxin to be helpful due to rapid absorption. If very recent ingestion then emesis and activated charcoal are indicated. o Greater risk of aspiration in a patient with a depressed swallow reflex. Contraindicated if unprotected airway if gag is absent • Warm gastric lavage if vomiting had no occurred and known ingestion • Rinse mouth thoroughly with water especially in cases where a dog has played with or chewed a fish

Symptomatic and supportive treatment in proportion to the clinical signs • The patients are normally profoundly paralysied and require immediate intubation and positive pressure ventilation (manual or mechanical) for 6-12 hours. • Respiratory support o Oxygen supplementation o Care - hypoventilation may cause severe hypercapnia • Immediate intubation and PPV if respiratory muscle paralysis and imminent respiratory arrest. Hypoxaemia PaO2 <60mmHg, Hypercapnia PaCO2 >60mmHg or unsustainable respiratory effort o Care – provide anxiolytics as these patients can be completely paralysised yet still know what is going on • Fluid resuscitation +/- vasopressors is persistent hypotenion • Atropine is not effective against tetrodoxin-induced bradycardia

Nursing care • Maintain normothermia • Monitor ins and outs • Padded bedding • Maintain sternal with regular physio and repositioning • Eye lubrication • Mouth care • Bladder care • Colon Care

Anti-cholinesterase drugs • Neostigmine or Edrophonium (Tensilon-too short acting in the dog) o Not clinically proven in humans or domestic pets o In humans, anecdotally effective in reversing muscle weakness especially if given earlier in course. Theoretically only if partial block as does not antagonise the block induced by TTX o Inhibits destruction of acetylcholine by acetylcholinesterase, which facilitates transmission of impulses across the myoneural junction o Repeat doses based on the patient’s response o Atropine antagonises muscarinic effects PROGNOSIS • Some animals have suffered severe toxicosis from biting or holding the fish, while others have had only mild signs from eating several • Suggested mortality varies from 0-70% depending on the source • Recovery is unlikely with 3rd degree heart block • Generally, once the patient survives 24 hours, the prognosis is good

Human Stages Immediate Slight numbness of lips and tongue Stage 1 Increasing paresthesia in face and extremities Sensations of lightness and floating Headache, nausea, severe abdominal pain, diarrhoea and/or vomiting Stage 2 Increasing paralysis Motor dysfunction with weakness, hypoventilation and speech difficulties Convulsions, mental impairment, cardiac dysfunction Stage 3 Central nervous system (CNS) dysfunction Complete paralysis Death (usually occurs between a range of 20 minutes to 8 hours, where a person could still be conscious or in certain cases completely lucid before death)

References: 1. Zimmer T. Effects of Tetrodotoxin on the Mammalian Cardiovascular System. Marine Drugs. 2010;8(3):741-762 2. Isbister GK, Et al. Puffer fish poisoning: a potentially life-threatening condition, Med J Aust. 2002 Dec 2-16; 177(11-12): 650-3. 3. Platt S, Garosi L. Small Animal Neurological Emergencies. 2012 4. Tetrodotoxin. Wikipedia 5. Sun KO. Management of Puffer Fish Poisoning. British Journal of Anesthesia 1995; 75:500 6. Benzer T. Tetrodotoxin Toxicity. Medscape. Dec 2015 7. Ahasan AM, Et al. Paralytic Complications of Puffer Fish (Tetrodotoxin) Poisoning. Singapore Med J. 2004 Vol. 45(2): 73