Intoxication is a common clinical presentation in first-opinion practice with numerous toxins that can lead to neurological signs, either by primary effect on the nervous system or secondary effect involving other organs. Neurotoxicity can manifest in many ways such as abnormal behaviour, tremors, ataxia, seizures and altered mental status. The exact toxin ingested is not always known, and therefore the diagnosis is often based on clinical history (known toxin exposure), and/or clinical signs consistent with exposure and appropriate diagnostic testing. Treatment in the emergency setting is often based on a presumptive diagnosis of toxin exposure, empirical treatment and assessment of clinical response.
There are several mechanisms where an intoxication leads to neurological signs in our veterinary patients. This may be termed “exogenous” where toxins from outside the body (eg plants, pesticides, medications) have a primary direct action on structures of the neurological system or “endogenous” as a result of organ dysfunction such as hepatic or uraemic encephalopathy (Platt and Garosi, 2012).
Neurotoxins can also be classified as neuroexcitatory or neuroinhibitory. Excitatory toxins typically cause hyper-excitability, seizures, muscle tremors, fasciculations and ataxia. Secondary complications include hyperthermia, disseminated intravascular coagulation (DIC), rhabdomyolysis and aspiration pneumonia. Neuroinhibitory toxins typically cause obtundation, stupor and coma, and/or weakness or flaccid paralysis leading to respiratory failure (Platt and Garosi, 2012). Prompt recognition and appropriate emergency treatment is required to ensure a good outcome.
Clinical approach to a suspected intoxication
Taking a history
It is important to take a thorough clinical history to assess the likelihood of intoxication. Owners may suspect toxin exposure when this is not the case. It is important to consider the history and clinical presentation to determine the likelihood of toxin exposure. Typically, the signs are acute in onset in a previously clinically normal animal.
It may be possible to discount a toxin as a cause of the neurological signs if, for example, the patient presents with a progressive neurological presentation (over days to weeks), or following multiple seizure events, which occur over a period of time. If the toxin is known, exact ingredients, possible dosage exposed to and timing of exposure should be ascertained on admission. Some owners may be reluctant to provide this information in the case of illegal substance exposure, in which case it is worth explaining the possible detrimental risk to the patient if treatment is delayed to encourage an honest discussion.
It is important to fully assess the patient; the cardiovascular system should be assessed by chest auscultation, mucous membrane assessment and palpation of peripheral pulses to assess rate, rhythm and pulse quality. Hypovolaemia should be corrected with fluid resuscitation and specific rhythm abnormalities confirmed by ECG before initiating appropriate treatment. Mean arterial blood pressure should be maintained above 70mmHg. Respiratory rate and effort should be assessed and, in cases of respiratory compromise, a patent airway secured and ventilation provided.
In the majority of cases, a rapid diagnosis is not possible and treatment is presumptive and supportive. Blood sampling should be performed, with a minimum emergency database, if not a comprehensive haematology and serum biochemistry performed. This may assist in identifying abnormalities that indicate a specific toxin. Alterations would be expected if a toxin affects other organs concurrently with the nervous system or if the organ impacted by the toxin indirectly leads to neurological dysfunction. Examples include acid-base disturbance such as metabolic acidosis and calcium oxalate monohydrate crystalluria in cases of ethylene glycol toxicity, severe azotaemia in uraemic encephalopathy, elevated liver parameters (including bile acid and ammonia) in hepatic encephalopathy, prolonged PT/APTT and activated clotting times in coagulopathies and severe hypoglycaemia in cases of xylitol toxicity. It is recommended to take plasma, serum and urine samples for freezing which may then be sent to an external laboratory for comprehensive toxicology. This can take between 1 and 10 days, so treatment should not be delayed until results are received. If vomiting is a clinical feature or is induced as part of the treatment (see treatment below), the vomitus may also be visually inspected and a diagnosis made, or material frozen for analysis.
Treatment of a suspected intoxication
Although treatment should be individualised, a standardised approach should be employed (Figure 1).
Stabilisation of vital parameters and neurological signs
The patient must be assessed and any immediate treatment administered if required. Possible neurological scenarios where emergency treatment is required include seizure management, severe neuromuscular signs with subsequent respiratory failure or raised intracranial pressure. The latter, although unlikely following neurointoxication, may be suspected if there is reduced mental status with Cushing’s response, which includes bradycardia, hypertension and an abnormal breathing pattern. Assessment may also be made using the Modified Glasgow Coma Scale, including pupillary light and oculocephalic reflexes. If elevation in intracranial pressure is suspected, treatment should be initiated with either mannitol (0.25 to 1g/kg of 10 percent solution over 20 to 30 minutes) or 7 percent hypertonic saline (4ml/kg in dogs, 2ml/kg in cats IV over 15 minutes) and the head elevated to encourage venous drainage. Care should be taken in cases of hypovolaemia, concurrent kidney injury or electrolyte imbalance. You should always follow these with isotonic fluids to prevent hypovolaemia.
Seizures are a common clinical sign of neurotoxicity and managing these correctly and swiftly is vital to avoid complications, such as long-term cerebral injury or heat stroke. Box 1 shows our simple way to remember the fundamentals of seizure management and drugs that may be used. If the patient is actively tremoring or showing evidence of muscle fasciculations, methocarbamol may be used, either by an IV or oral preparation (44 to 220mg/kg IV, given in boluses of 30 to 40mg/kg to a maximum of 330mg/kg/day (Platt and Garosi, 2012) or 20 to 45mg/kg PO every 8 hours (BSAVA, 2015)). If the patient is comatose or lacking a gag reflex, the oral preparation may be diluted in water and given rectally. This is particularly useful in cases of tremorgenic mycotoxins following ingestion of mouldy food.
Intravenous benzodiazepines may also be considered as anti-epileptic therapy (Box 1), for skeletal muscle relaxation, anxiolysis and sedative effects. Care must be taken in cases of hepatic damage due to their metabolism by the liver and possible worsening of hepatic encephalopathy. Also beware of the risk of acute hepatic fulminant necrosis in cats reported following repeated administration.
|Our A to E of seizure management:|
A. Airway must be secured via mask or intubation and administer 100 percent oxygen
B. Bloods should be taken for minimum emergency database including glucose and electrolytes. Jugular sampling should be avoided
C. Cool the patient slowly if hyperthermic (more than 40°C) and continually monitor temperature
D. Drugs to control seizures should be given intravenously. If no venous access is available: midazolam 0.2mg/kg intramuscular or intranasal OR diazepam 0.5mg/kg intrarectal
E. Elevate the head at approximately 30° angle
Further control of seizure management includes:
1. Midazolam 0.2mg/kg IV/IN/IM, 0.3mg/kg/hr CRI) or diazepam (0.5mg/kg IV/PR, 0.5 to 2mg/kg/hr CRI). Boluses may be repeated up to three times q10 minutes, followed by CRI
2. Levetiracetam: 40 to 60mg/kg bolus IV or PR, followed by 20mg/kg IV every 8 hours
3. Phenobarbitone: Loading dose 24mg/kg IV over 24 hours divided into 3 to 6mg/kg doses
4. Ketamine: 250 to 500mcg/kg IV bolus followed by 3 to 10mcg/kg/min CRI
5. Propofol: 0.1 to 0.2mg/kg/min CRI
Prevent continued absorption of the poison
We must consider continued absorption of the toxin. The benefit of this is often dictated by the time between toxin exposure and presentation and is typically performed by inducing emesis or by gastric lavage usually within three hours of ingestion. Contraindications to emesis include altered mentation, loss of gag reflex, seizures, coma or ingestion of caustic substances. Alternatively, if toxin ingestion is recent and emesis is deemed contraindicated, gastric lavage may be considered under general anaesthesia with intubation to ensure a secure and patent airway. It is important to stabilise the patient prior to anaesthesia and a risk-benefit assessment made on the risks of an anaesthetic versus continued absorption of the toxin. If there is a delay between ingestion and presentation to your clinic, a colonic enema may be considered; however, this is rarely of use. In mild intoxications, treatment with activated charcoal alone may be sufficient.
Enhance elimination of the absorbed poison
Attempts must be made to enhance the clearance of the ingested toxin. Intravenous fluid therapy is indicated to ensure diuresis (based on the individual patient, but at a minimum maintenance therapy at 2ml/kg/hr). Care must be taken in patients with concurrent cardiac disease, hypertension or acute renal failure. Placement of a urinary catheter should be considered, and can often be performed without sedation in males, to accurately measure urinary output. This is particularly of use following chocolate ingestion due to the continued absorption of metabolites across the bladder wall. A metoclopramide continuous rate infusion (CRI) at 1 to 2mg/kg/day may also be used to increase gut motility and reduce transit time.
Administer a specific antidote
In addition to the general management of intoxication, administration of specific antidotes may be possible if the toxicity is known or suspected and an antidote is available (see emergency texts for details of specific antidotes). A particular consideration in the treatment of a neurological patient is the use of intravenous intralipid emulsion therapy (IVLE). There remains debate on the exact mechanism of the treatment; however, we may assume in many cases of neurotoxicity, clinical signs result from lipid-soluble toxins crossing the blood-brain barrier, and therefore using a therapy which reduces the tissue concentration of any lipid-soluble toxicant, as is the case with intralipids, should be of benefit. The risks of its use are very low but include corneal lipidosis, fat overload syndrome and pancreatitis (Robben and Dijkman, 2017) and it should always be administered using a filter to reduce the risk of fat emboli. Notable neurotoxins where it is of benefit include ivermectins, permethrin, tremorgenic mycotoxins and recreational drugs. Dosage is usually an initial IV bolus of 2ml/kg, followed by a CRI of 4ml/kg/hour for four hours. This can be repeated if appropriate (Platt and Garosi, 2012).
Providing supportive care
Patients presenting with severe neurological signs may have altered mentation (obtundation, stuporous or comatose), or require sedation and/or mechanical ventilation. Intensive nursing of the recumbent patient may be required and it plays a vital role in the recovery of the patient and prevention of further complications.
- Obtunded patients or those at risk of aspiration (systemic neuromuscular disease) should be intubated with a cuffed endotracheal tube. For prolonged periods of intubation, the cuff should be deflated, repositioned and then reinflated. The endotracheal tube and the oropharynx should be suctioned regularly. The tongue should be moistened regularly to prevent drying and ulceration
- Normovolaemia should be maintained and hydration corrected. Consider any fluid losses, including vomiting/diarrhoea, the effect of administered drugs (diuresis by mannitol or hypertonic saline) and prolonged anaesthesia with subsequent free water loss from respiratory mucosa (particularly when the ventilator circuit is not humidified)
- Normothermia should be maintained. Aggressive active cooling should be initiated if the patient is hyperthermic (rectal temperature greater than 40°C/104°F) until the rectal temperature is 39.7°C (103.5°F). Cooling via convection is the most effective way (wetting animal or use of cool fan). Use of ice packs can cause cutaneous vasoconstriction and slow cooling. Wet towels will impair evaporative losses. Patients with hypothermia should be slowly corrected with frequent reassessment of temperature. It is important to continually monitor circulation parameters (heart rate/rhythm, blood pressure) as well as metabolic state (particularly blood glucose concentration). Warming is most effective via circulating warm air blankets
- Patients that have ingested a caustic substance or are at risk of gastrointestinal mucosal damage or oesophagitis will likely benefit from gastro-protectant treatment. Commonly used medications include omeprazole (1mg/kg IV/PO) or sucralfate (500mg/dog q6 to 8 hours PO (up to 20kg), 1 to 2g/dog q6 to 8 hours (more than 20 kg), 250mg/cat q8 to 12 hours PO) (BSAVA, 2015). Anti-emetics may also be considered such as maropitant (1mg/kg IV/SC) or metoclopramide (0.5mg/kg IV/IM/SC)
- Patients that have ingested a caustic substance orare at risk of gastrointestinal mucosal damage or oesophagitis will likely benefit from gastro-protectant treatment. Commonly used medications include omeprazole (1mg/kg IV/PO) or sucralfate (500mg/dog q6 to 8 hours PO (up to 20kg), 1 to 2g/dog q6 to 8 hours (more than 20 kg), 250mg/cat q8 to 12 hours PO) (BSAVA, 2015). Anti-emetics may also be considered such as maropitant (1mg/kg IV/SC) or metoclopramide (0.5mg/kg IV/IM/SC)
- The patients should be turned every four hours to prevent pressure sores, and padded bedding provided
- Patients should be supported in sternal recumbency with regular oxygenation monitoring. There is a high risk for atelectasis leading to hypoxaemia if in lateral recumbency for prolonged periods of time
- Daily physiotherapy should be performed, such as passive range of motion of the limbs
- The bladder must be effectively managed either by regular expression or catheterisation. If the latter, aseptic technique should be used with a closed system. Urinary output can be accurately calculated, and should aim for between 1 and 2ml/kg/hr
- Patients with impaired ability to blink will require ocular lubricants applied at least every four hours to prevent complications such as corneal ulceration from prolonged exposure
A logical approach should be taken to manage any intoxicated patient, with particular consideration to those patients presenting with specific neurological signs such as tremors, mentation changes, ataxia, blindness and seizures. Prompt management of life-threatening complications such as status epilepticus and elevated intracranial pressure must be initiated, and steps taken to prevent secondary morbidities. Often those patients with neuro-intoxication can be the most challenging and require intensive nursing care, but can also be the most rewarding.