Background: Intoxication resulting in severe derangements in the neurological and cardiovascular systems can be life threatening and it is important to know how to stabilise and support affected patients.
Aim of the article: This article is the second in a series of four. It discusses specific toxicants that affect the neurological and cardiovascular systems and outlines principles for managing patients presenting with the consequences of intoxication.
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Erica Tinson qualified from the University of Melbourne in 2008 where she also completed a residency in small animal emergency and critical care. She is a lecturer in small animal emergency and critical care at the Royal Veterinary College.
Simon Cook qualified from the University of Bristol in 2011, completing an internship and residency in small animal emergency and critical care at the Royal Veterinary College in 2017. He is a lecturer in small animal emergency and critical care at the RVC.
Key learning outcomes
After reading this article, you should understand:
The pathophysiology behind common neurological and cardiovascular intoxications;
Common toxicants affecting the neurological and cardiovascular systems;
The structured approach to neurologically and cardiovascularly intoxicated patients and their management;
The indications for common antidotes and lipid emulsion therapy in both cardiovascular and neurological intoxications.
The first article in this series discussed the basic approach to decontamination of the asymptomatic patient exposed to a toxicant (Humm and Greensmith 2019). This article will focus specifically on toxicants that affect the neurological and cardiovascular systems. While numerous potential toxicants are discussed, specific toxic doses are not included and contact with the Veterinary Poisons Information Service (www.vpisglobal.com) is advised to allow discussion on a case-by-case basis.
Neurotoxicants can affect the central or peripheral nervous system (CNS or PNS) directly or indirectly. Indirect consequences occur when the primary target is neither the CNS nor PNS, but another system within the body. Examples of indirect neurological effects of toxicants include:
Hepatotoxicity causing hepatic encephalopathy or hypoglycaemia (eg, Amanita mushroom intoxication);
Insulin release and hypoglycaemia (eg, xylitol);
Severe hypo/hypertension altering mental status (eg, β-blocker and calcium channel blocker toxicity);
Metabolic shock (eg, in methaemoglobinaemia).
The onset of action and progression in direct neurotoxicities are normally very rapid. However, this is not always the case, with lead and macadamia nut ingestion being examples of direct neurotoxicants that can cause a more delayed onset of clinical signs (Cortinovis and Caloni 2016).
Neurological signs of intoxication are often classified as predominantly excitatory or inhibitory. Excitatory effects on the CNS include hyperexcitability, hyperaesthesia and seizures, while excitatory effects on the PNS include muscle tremors, fasciculations and occasionally ataxia. Inhibitory effects on the CNS include obtundation, stupor and coma; inhibitory effects on the PNS include weakness, flaccid paralysis and respiratory depression when severe.
Some toxins can cause either hyperexcitability or inhibition depending on the dose (eg, amitraz) or can progress from excitatory to inhibitory over time. Alternatively, patients might transition between a hyperexcitable and an inhibited state (eg, marijuana toxicity), depending on the degree of environmental stimulation. Table 1 details the common clinical signs associated with specific intoxications.
Initial management of neurointoxication
Major body systems assessment
Because the clinical signs of neurointoxication can progress rapidly, prompt evaluation of the patient is necessary, even in non-symptomatic patients. In a symptomatic patient (seizing, tremoring or obtunded), the initial examination might need to be delayed until an intravenous catheter is placed. This will allow timely control of excitatory signs and help facilitate the delivery of anaesthetic agents if endotracheal intubation is required. Once the initial signs of intoxication are managed, a physical examination can follow.
Baseline blood samples should be collected from the intravenous catheter before treatment because some medications (diazepam or activated charcoal) can interfere with point-of-care tests (eg, ethylene glycol snap test) (Eder and others 1998).
With the cardiovascular system also commonly affected by neurotoxicants, blood pressure measurement and an electrocardiogram (ECG) should be included in the initial evaluation.
The mucous membranes should be carefully examined as certain neurotoxicants will cause alterations in their colour, such as cyanide (cyanosis) and carbon monoxide (cherry red).
Respiratory patterns (and where possible, venous or arterial blood gas samples) should be analysed because neuroinhibited patients may hypoventilate. There are also certain neurotoxicants that can cause respiratory paralysis (nicotine, acetylcholinesterase inhibitors, cyanobacteria) (Tse and others 2013).
All patients (whether inhibited or hyperexcitable) are predisposed to aspiration events; thoracic auscultation and point-of-care ultrasound should therefore be performed repeatedly (Fig 1).
In both inhibited and hyperexcitable patients, body temperature may be altered (hypothermia and hyperthermia, respectively).
Stabilisation of neurological signs
In the actively seizing patient, diazepam or midazolam are the first-line therapy (Table 2). In patients refractory to intravenous benzodiazepines, propofol can be used to control the visible muscular activity but an antiepileptic drug such as phenobarbitone or levetiracetam must be used concurrently to control the underlying seizure activity. Some authorities advocate the use of levetiracetam over phenobarbitone to limit the degree of sedation. In some cases however, the sedative effects can be beneficial.
A constant rate infusion (CRI) of benzodiazepines can be used in cases with ongoing seizure activity. Cases with persistent seizures or those remaining in status epilepticus will benefit from this approach. Propofol infusions can be added to control ongoing muscular activity.
Benzodiazepines may occasionally cause disinhibition and exacerbate hyperaesthesia. It may then be necessary to administer additional sedation until these effects subside. There are certain situations where benzodiazepines should be avoided (serotonin syndrome and amphetamine intoxication).
If the patient is tremoring rather than seizing, methocarbamol will be more appropriate. Guaifenesin can be used where intravenous methocarbamol is not available. Alternatively, oral methocarbamol tablets can be crushed, dissolved in water, and administered per rectum. Methocarbamol can be combined with diazepam for additional muscle relaxation effects.
To control CNS excitation, tranquillisers such as acepromazine (0.005–0.05 mg/kg intravenously) may be required. These can be particularly useful in cases of methylxanthine, marijuana and amphetamine toxicity. It is important to consider the patient’s haemodynamic status when choosing a sedative to control CNS excitation. Combining low doses of acepromazine (0.005 mg/kg) and butorphanol (0.1–0.2 mg/kg intravenously) or even the addition of a butorphanol CRI can be useful.
Patients with seizures or tremors may become hyperthermic. When the rectal temperature is ≥40°C (104°F), the patient should be aggressively cooled. This is best achieved using convective cooling – wetting the skin and coat with cool water and using an electric fan (towels should not be applied as they act as blankets preventing evaporative loss). Active cooling should stop when a rectal temperature of 39.7°C (103.5°F) is reached to avoid hypothermia as patients may also have poor thermoregulation. More aggressive methods of active cooling may be necessary in cases suffering from malignant hyperthermia (eg, hop ingestion). Depressed patients are more likely to be hypothermic and will require active warming.
Stabilisation of major body system concerns
Intravenous fluid therapy with isotonic, balanced crystalloids (compound sodium lactate, Normosol R [ICU Medical], Plasma-lyte [Baxter International]) is indicated in most cases for resuscitative and ongoing fluid requirements. Fluid losses will be increased in patients receiving mannitol or cathartics as part of their management and ongoing fluid rates will need to account for this.
Fluid therapy is particularly important for neurotoxicants known to cause renal injury (eg, lead) and also in cases suffering rhabdomyolysis with pigmenturia as a result of severe excitatory signs, as myoglobinuria can cause acute kidney injury.
Oxygen therapy could be required in cases suffering from respiratory depression, aspiratory pneumonia/pneumonitis or non-cardiogenic pulmonary oedema (seen with severe seizures). Specific toxicants resulting in tissue hypoxia and neurological signs include carbon monoxide and cyanide.
The methods of oxygen supplementation used will depend on the severity of hypoxaemia; however, intranasal cannulae should be avoided if there are concerns over raised intracranial pressure (to minimise the risk of sneezing). A severely depressed patient with a poor gag reflex will need airway protection using a cuffed endotracheal tube. This might also be the case if the depression is iatrogenic during seizure management.
Intravenous lipid emulsion (IVLE) therapy can be used in most cases, because of its wide safety margin (see Humm and Greensmith 2019). It should be considered when a lipid-soluble toxicant is suspected and has been used in veterinary patients intoxicated with macrocyclic lactones, permethrins, local anaesthetics, serotonergic drugs and muscle relaxants (baclofen) (Feldman and others 1991, Haworth and Smart 2012, Kaplan and Whelan 2012, Epstein and Hollingsworth 2013, Kormpou and others 2018).
Mannitol or hypertonic saline should be used in cases when raised intracranial pressure is suspected (Cushing’s reflex, deteriorating mental status) and cerebral oedema is highly likely; for example, in bromethalin, lead and water intoxication (Platt and Garosi 2012).
Certain toxicities (ethanol, ethylene glycol) can result in a severe metabolic acidosis. Sodium bicarbonate can be considered when the venous blood pH is <7.1, particularly if renal function is impaired (Table 2). Bicarbonate therapy has also been advocated to alkalinise urine in an effort to ion trap certain agents and aid with removal (eg, phenobarbitone, salicylates, cyclic antidepressants). Risks with this therapy in this setting include paradoxical central acidosis and cerebral vasodilation impairing autoregulation of blood flow to the brain.
Available antidotes for neurotoxicants include atropine, which is indicated for toxins exacerbating muscarinic signs (acetylcholinesterase inhibitors), and pralidoxime (2-PAM), which is used to reverse the nicotinic signs in organophosphate poisoning (but is contraindicated in carbamate toxicity).
Chelation agents (succimer) are available for lead toxicity; however, these are not indicated until the source of lead has been removed from the gastrointestinal tract.
Inhibition of alcohol dehydrogenase using ethanol or 4-methylpyrazole (fomepizole) is extremely unlikely to be beneficial in ethylene glycol toxicity unless performed within three to four hours of ingestion (Bates and others 2015). The lack of availability of fomepizole in many countries (including the UK) means that ethanol would need to be used.
In certain neurotoxicities, other supplements can be considered. Lead toxicity might respond to thiamine and zinc supplementation.
Because neurointoxications often present very shortly after exposure, decontamination through emesis induction can be an important part of therapy. Generally, it is suggested that emesis is induced within two hours of ingestion (Humm and Greensmith 2019), but this depends on many factors, including the toxicant being considered. Chocolate ingestion, for example, can cause delayed gastric emptying so can be recovered by emesis up to 12 hours after ingestion.
Emesis should not be attempted in overtly clinical patients (moderate to severe tremors, seizing or reduced mentation) as there is a risk of aspiration. Moreover, emesis can result in raised intracranial pressure. Inducing emesis can also worsen clinical signs in neurotoxicities that cause hyperaesthesia, tremors or muscle spasms (eg, strychnine, cyclic antidepressants).
If the patient is overtly clinical (profound CNS depression or neuroexcitation), vomiting has not already occurred and recent ingestion of a lethal dose of toxicant is suspected, gastric lavage is indicated. Colonic lavage can be considered in the peracute stages of management in some neurotoxicants (organophosphates and carbamates) because they course rapidly through the gastrointestinal tract.
Certain neurotoxicants may not bind to charcoal or charcoal may be contraindicated. These include salt (NaCl), xylitol, alcohols (methanol, ethanol, ethylene glycol), petroleum products, strong acids or alkalis and dissociable salts (lithium) (Cortinovis and Caloni 2016).
Some neurotoxicants may be absorbed via dermal exposure (eg, pyrethroids and anticholinesterases) and the animal will need to be clipped and washed with a mild detergent to remove these agents.
Baseline bloods will allow monitoring of potential hepatic, renal and haematological consequences of intoxication. When the toxicant is known, a more targeted choice of blood analysis can be performed – for example, monitoring a renal profile when ibuprofen toxicity is suspected, or a liver profile in xylitol toxicity.
Venous blood gas analysis can reveal derangements indicative of neurointoxications. An increased anion gap, normochloraemic, metabolic acidosis can be seen in paracetamol (acetaminophen), salicylate, cyanide, methanol, ethylene glycol and cyanide toxicities (Means 2003). A metabolic acidosis is common in cases of metaldehyde toxicity and hyperlactataemia can be seen in cyanide and ethylene glycol toxicity (Silverstein and Hopper 2009, Platt and Garosi 2012). The elevated lactate in ethylene glycol toxicity occurs when analysers (eg, Radiometer ABL; Radiometer) that measure L-lactate cross react with ethylene glycol metabolites. Some analysers will not cross react with the metabolites (i-STAT; Abbott) and so a ‘lactate gap’ can be seen between the two methods (Brindley and others 2007).
An elevated venous oxygen saturation (>70 per cent) or a decrease in arterial-venous oxygen saturation difference could also indicate cyanide toxicity (Silverstein and Hopper 2009).
Co-oximetry on blood gas analysers will allow carbon monoxide levels to be evaluated.
Ethylene glycol toxicity will cause an increase in the osmolar gap (osmolar gap = measured – calculated osmolarity) for up to 18 hours after ingestion; however, osmometry is rarely available to assess this.
Plasma sodium concentration will be elevated in salt intoxication and paintball ingestion and reduced in water intoxication and should be part of the initial evaluation.
Other parameters that should be evaluated are glucose and ionised calcium as these could be altered in ethylene glycol toxicity (hyperglycaemia and hypocalcaemia) and xylitol (hypoglycaemia) ingestion (Platt and Garosi 2012).
A point-of-care blood test for ethylene glycol is available (Kacey EG Test Strips; Kacey) but false positives are possible, and it is less reliable in cats (Eder and others 1998). A simple test (although variably reliable) to support ethylene glycol ingestion is positive fluorescence by Wood’s lamp examination of vomitus or urine (up to six hours after intoxication). Urine can be examined for calcium oxalate monohydrate crystalluria which is seen within three to six hours of ethylene glycol intoxication.
Human urine drug test kits (available in pharmacies) can be used to screen for recreational drug intoxications but need to be interpreted with caution as they are not validated for use in animals.
Diagnostic/confirmatory testing on body fluids such as blood, vomitus and urine are increasingly available with 24-hour turnaround times from commercial veterinary laboratories. Extensive toxicology panels are offered by the Veterinary Pathology Group at SynLab. Unfortunately, there are few antidotes available in veterinary toxicology, meaning that the value in identifying the toxicant is not necessarily in finding an antidote, but more to enable anticipation of other systemic effects and to determine prognosis. Confirming that a toxin is the cause of the clinical signs also means that effort can be saved on surplus diagnostic investigations.
Common toxicants directly affecting the neurological system
Cannabinoids (marijuana, cannabidiol and synthetic cannabinoids)
There are a growing number of sources from which pets can be exposed to cannabinoids. These include marijuana, cannabidiol (CBD) and synthetic cannabinoids (SCBs). Marijuana is a dried preparation of the leaves and stems of the plant Cannabis sativa. CBD is a non-psychoactive cannabinoid sold commonly for health benefits (sometimes as an oil) while SCBs are sold for recreational use (Brutlag and Hommerding 2018) and are known by many names including spice, K2, black-mamba, skunk and zombie.
The active cannabinoid in marijuana is 9-tetrahydrocannabinol (THC) which binds a cannabinoid receptor (C1) centrally and thus inhibits the release of multiple neurotransmitters including acetylcholine, glutamate, gamma aminobutyric acid (GABA), norepinephrine, dopamine and 5-hydroxytryptamine (5-HT) (Drobatz and others 2018). SCBs will also bind this receptor but with greater affinity and potency. CBD is non-psychoactive because it does not bind to the C1 receptor.
The most common route of exposure to cannabinoids is ingestion and onset of clinical signs is usually seen within one to two hours (Drobatz and others 2018). Clinical signs in marijuana toxicity include ataxia, depression, altered mentation, hypersalivation, mydriasis, nystagmus, bradycardia, hyperaesthesia, urinary incontinence and coma. Because CBD does not bind the C1 cannabinoid receptor, less severe signs are expected with overdose compared to THC-containing products. Some CBD products can, however, also contain THC (usually in low concentrations), even when not listed in the ingredients (NHS 2018).
Due to the high potency of SCBs for the C1 receptor, more extreme clinical signs than in marijuana toxicity are expected, but clinical effects data are limited for veterinary species.
Treatment for cannabinoid toxicity is mostly supportive. Fatalities are rare for marijuana intoxication and unlikely with CBD; however, based on human reports, they are more likely with SCBs (Drobatz and others 2018). An awareness of the different types of cannabinoids available is therefore important. Repeat doses of activated charcoal should be given due to enterohepatic circulation. IVLE therapy should also be given due to the lipophilicity of THC.
Pyrethrins and pyrethroids (derivatives of pyrethrins) are insecticides used commonly in veterinary medicine for flea control. The main source of toxicity in clinical practice is when dog flea treatments are applied to cats. Dermal absorption occurs but most of the bioavailability of the agent occurs when it is groomed off the fur.
The toxic effects are elicited through interaction of the agent with voltage-sensitive sodium channels. Clinical signs typically occur within a few minutes but may be delayed up to 72 hours (Silverstein and Hopper 2009). These signs include tremors, hyperexcitability, hypersalivation, seizures and depression.
Decontamination requires bathing in warm water with a mild detergent. Hypersalivation could indicate oral exposure and general gastrointestinal decontamination guidelines apply. Enterohepatic circulation occurs with some pyrethroids. Treatment is supportive and aimed at controlling tremors and seizures. IVLE therapy should be used in these cases as there is an evidence base for its benefit (Peacock and others 2015).
Decomposing food (commonly bread, vegetables, cheese and nuts) contain multiple different tremorgenic mycotoxins, produced by Penicillium fungi. The most common mycotoxins affecting dogs are penitrem A and roquefortine. Their mechanism of action is largely unknown but is possibly through inhibition of glycine in inhibitory neurons (Platt and Garosi 2012).
Clinical signs of generalised, progressive tremors are typically sudden onset and can resemble a seizure. Salivation, panting and hyperthermia can also be features.
Emesis is rarely safe and, as the risks probably outweigh the benefits, we would not recommend gastric lavage. Sedation and muscle relaxation are the mainstays of treatment, with antiepileptic medications proving useful for their sedative effects. Intubation is often performed in severe cases when sedation compromises airway protection. IVLE therapy should be given due to the lipophilic nature of the toxins (Kormpou and others 2018).
The recent overturning of plans to ban metaldehyde use in the UK will mean continued exposure of pets to this agent (Bradbury 2019). Used for baiting slugs and snails it decreases levels of the inhibitory neurotransmitter GABA, increases monoamine oxidase activity and decreases noradrenaline and serotonin levels (Platt and Garosi 2012). Metaldehyde is absorbed via the gastrointestinal tract and induces initial anxiety, followed by tremors, ataxia, muscle fasciculations and seizures. Temporary blindness is also reported (Firth 1992).
With effective decontamination (including gastric lavage and enema), treatment for prolonged periods is generally not required and the majority of management is focused on controlling tremors and hyperaesthesia. Activated charcoal can limit absorption but the rapid progression of clinical signs often prevents its use due to the risk of aspiration.
Bromethalin is gaining popularity as a rodenticide in the USA and although not commonly used in the UK, it is currently available (Lyons and others 2019). Its mechanism of action is different from the anticoagulant rodenticides (eg, brodifacoum). Once ingested, bromethalin uncouples oxidative phosphorylation, resulting in a complete failure of mitochondrial ATP production. The most important manifestation is in cell membrane sodium/potassium ATPase pump failure.
Clinical signs are usually apparent within two hours of ingestion, but low doses could result in a delayed presentation. Signs include ataxia, depression, seizure, coma, respiratory paralysis and death.
The toxin is very rapidly absorbed, and decontamination is of questionable benefit beyond one-and-a-half hours after exposure. There is no antidote, treatment is largely supportive and the prognosis is extremely guarded. Enterohepatic circulation occurs, which warrants the use of activated charcoal if clinical signs are not present. Specific treatment for cerebral oedema is indicated, and IVLE therapy should be considered. Ginko biloba was used with success in conjunction with other treatments in one report, and has also been shown to provide some protective effect in experimental rat models (Dorman and others 1992, Lyons and others 2019).
A number of common toxicants (Table 1) have the capacity to directly cause cardiovascular compromise. Perhaps more frequently, toxicants may cause cardiovascular changes indirectly, in which case the underlying toxicity and cause will require management alongside supportive therapies for the cardiovascular system. Indirect effects could include tachycardia, bradycardia, hypertension, hypotension and arrhythmias.
During a major body systems assessment focusing on controlling seizures, securing oxygenation/ventilation and airway protection, cardiovascular priorities common to all intoxications would include intravascular volume resuscitation where necessary, monitoring and correcting electrolyte derangements and continuous ECG and blood pressure monitoring. It is important to have excluded hypovolaemia before any form of sedatives or β-blocking agents are used, and careful consideration should be given to potential fluid losses when taking a history and carrying out a physical examination.
Tachycardia may simply result from endogenous catecholamine release, which may stem from the stress of the episode or clinical signs, hospitalisation or discomfort associated with intoxication. Hyperthermia, which may be apparent in many neurotoxicities, has the capacity to reduce peripheral vascular resistance, cardiac preload and cardiac output, with a resultant tachycardia that will respond to fluid resuscitation and active cooling (Miki and others 1983).
Tachycardia as a direct result of intoxication is common in amphetamine, cocaine and methylxanthine intoxications. Often the tachycardia is controlled with sedative drugs used to manage excitation, with β-blocking agents such as esmolol reserved for severe cases (Thomas and others 2014).
There are many reasons why an intoxicated patient may be bradycardic. Gastrointestinal dysfunction may elevate vagal tone; atrial standstill can develop due to hyperkalaemia in patients with acute kidney injury; and patients with raised intracranial pressure can develop hypertension and bradycardia.
It is crucial to measure blood pressure and evaluate an ECG in a patient with bradycardia and clinical signs before considering any form of intervention. For example, atropine would be contraindicated in the bradycardic, hypertensive patient with raised intracranial pressure.
Bradycardia as a direct result of intoxication would be common in marijuana, digoxin and β-blocker intoxications.
Hypertension is not a particularly common indirect manifestation of an intoxication, except in the event that raised intracranial pressure has developed (eg, after protracted seizures or cardiorespiratory arrest and development of cerebral oedema). It may be more commonly documented in excitatory and sympatheticomimetic intoxications such as with methylxanthines, amphetamines and cocaine. It will rarely necessitate antihypertensive treatment beyond sedation and β-blocking agents where tachycardia is also present. Phenothiazines such as acepromazine would serve as sedatives and antihypertensives concurrently.
Hypotension is commonly encountered in the intoxicated patient, most likely because of a loss of vasomotor tone (including iatrogenically during treatment), with or without concurrent loss of intravascular volume (eg, in patients with vomiting and diarrhoea).
Fluid resuscitation and ongoing fluid therapy would be the mainstays of management in this scenario, but if hypotension persists and loss of vasomotor tone is considered a significant factor, then vasopressor therapy should be instigated. The choice of vasopressor may come down to availability and familiarity, but noradrenaline or dopamine would be reasonable first-line choices. Dobutamine should be reserved for cases with cardiac systolic dysfunction and avoided where possible due to proarrhythmic properties.
It should be noted that all vasopressors have the potential to induce or worsen arrhythmias, and hence every attempt should be made to taper down and stop them as soon as they have served their purpose.
The most important rule in management of arrhythmias is ‘primum non nocere’ – ‘first do no harm’. If the arrhythmia is not compromising cardiac output, is improving with time, or the patient is not clinically affected, then it is unlikely that antiarrhythmic therapy is indicated. In the event that worsening ventricular arrhythmias (a common tachyarrhythmia seen in intoxicated patients) are documented, the indications for treatment with lidocaine would be sustained ventricular tachycardia (above 160–170 beats per minute [bpm]) (Fig 2), progressive, polymorphic ventricular rhythms and/or R-on-T phenomenon. Accelerated idioventricular rhythm (ventricular beats occurring at a rate above the ventricular escape rate of about 30–50 bpm up to 160–170 bpm in dogs) does not warrant antiarrhythmic treatment and the difference between this and true ventricular tachycardia is solely the rate.
Ventricular arrhythmias are often seen in amphetamine and local anaesthetic intoxications.
In the unknown but suspected intoxication with cardiovascular derangements, the first question to answer is whether the cardiac abnormalities are physiological responses or more likely toxicant-induced. Physiology can be managed by the supportive measures discussed earlier, while some toxicity-associated effects have particular remedies or management techniques.
Considering the tendency for cardiovascular toxicities to result from human medication ingestion, thankfully their identity and time of ingestion may be known more often than in neurological intoxications. To that effect, sometimes they have a more specific treatment protocol.
Common toxicants directly affecting the cardiovascular system
Methylxanthines (eg, theobromine and caffeine [chocolate])
There is a spectrum of clinical signs referable to chocolate ingestion, from initial gastrointestinal signs (vomiting and diarrhoea) within six hours of ingestion, through to agitation, tremors and associated hyperthermia, and tachycardia or tachyarrhythmias that could ultimately prove fatal.
Decontamination should be instigated by emesis so long as the patient is not neurologically affected, followed by repeated doses of activated charcoal. It is well worth sourcing a ‘chocolate calculator’ to help with a quick assessment of the risk of toxicity when consulted by telephone – dark chocolate contains significant amounts of methylxanthines compared to white and milk chocolate.
Treatment is largely supportive, including enhancement of urinary excretion of toxic metabolites with fluid therapy and promotion of urination, as methylxanthines can be reabsorbed across the bladder wall. The vast majority of cases will not require treatment for longer than 12 to 24 hours.
In severe cases with persistent sinus tachycardia, short-acting β1-selective blocking drugs such as esmolol may be used. This would be delivered as a CRI where ECG and blood pressure monitoring are available, as bradycardia and hypotension would be common adverse effects.
CNS signs (usually excitatory although seizures, coma and death are possible) are more common side effects of local anaesthetic toxicity when plasma levels rise slowly. However, when toxicity results from intravenous injection, a rapid rise in local anaesthetic levels can cause cardiovascular collapse. Local anaesthetics will prolong the QR interval and QRS complexes, induce bradycardia and atrioventricular blocks and predispose to ventricular arrhythmias.
Treatment is supportive (ie, supporting perfusion and oxygenation, avoiding electrolyte derangements and managing nausea) but IVLE therapy is specifically indicated in local anaesthetic overdoses, especially when cardiopulmonary resuscitation is being attempted (Fernandez and others 2011).
Calcium channel blockers and beta blockers
Calcium channel blockers
Calcium channel blockers are prescribed frequently in both human and veterinary medicine. There are three broad groups that predominantly have their effects on cardiac myocytes, pacemaker cells and vascular smooth muscle cells. The phenylalkylamines (eg, verapamil) and benzothiazepines (eg, diltiazem) tend to cause bradycardia by inhibition of L-type calcium channels in cardiac pacemaker cells and can cause negative inotropy concurrently. While all calcium channel blockers can cause vasodilation of peripheral and coronary vasculature, the dihydropyridines (eg, amlodipine, nicardipine and nifedipine) have the highest vasodilator potency. For these reasons, a diltiazem or verapamil intoxication is more likely to cause bradyarrhythmias and hypotension, rather than hypotension and associated tachycardia as seen in the case of an amlodipine intoxication.
In addition to cardiovascular collapse, calcium channel blockers impair insulin release, creating a hyperglycaemic state and a form of metabolic shock whereby intracellular glucose supplies are depleted.
β1 receptors are located primarily in the sinoatrial and atrioventricular nodes and myocardium and stimulation induces an increase in heart rate and contractility. β2 receptors are predominantly located in bronchial and vascular walls, where stimulation induces relaxation, and in the pancreas, where they promote insulin release.
β-blockers such as sotalol and propranolol block both β1 and β2 receptors, while esmolol and atenolol only block β1. β-blocker intoxication therefore reduces myocardial contractility, heart rate and atrioventricular conduction. When β2 blockade is also present, bronchoconstriction and inhibition of insulin release can also occur.
Ultimately both calcium channel blockers and β-blockers have the capacity to cause cardiovascular collapse by massive vasodilation, reduced chronotropy and reduced inotropy. Crucially, the downstream effect of β blockade is inhibition of L-type calcium cells in the heart, hence the mechanisms of toxicity and treatment of both classes are similar.
Management of calcium channel blocker and beta-blocker intoxications
Emesis would be recommended in asymptomatic patients, with gastric lavage reserved for cases with massive, recent ingestion, with or without an altered level of consciousness that precludes induction of emesis. Note that sustained-release formulations of calcium channel blockers may make repeated doses of activated charcoal useful (Laine and others 1997).
Alongside intravenous fluids (bolused in the hypotensive patient), intravenous calcium administration is recommended in both calcium channel blocker and β-blocker toxicities, to improve cardiac conduction, inotropy and blood pressure. Typically, 0.5–1 ml/kg of 10 per cent calcium gluconate would be administered (slowly to avoid hypotension and arrhythmias) followed by a CRI to secure high-normal serum calcium levels.
Adrenergic vasopressor drugs targeting increased cardiac contractility (eg, dobutamine, norepinephrine, dopamine) and increased vasomotor tone (norepinephrine, dopamine) may be indicated.
Insulin therapy is recommended as it will promote intracellular glucose uptake, allowing an increase in inotropy and peripheral vascular resistance. The recommended dose would be 1 iu/kg neutral insulin initially, followed by 1 iu/kg/hr for one hour, and 0.5 iu/kg/hr until no longer required (Engebretsen and others 2011).
Glucagon has also been recommended as it has inotropic, chronotropic and dromotropic effects on the heart. IVLE therapy is of theoretical benefit when traditional management is not effective. Calcium channel blockers and β-blockers are variably lipid soluble, however, with propranolol and verapamil being the most soluble.
Serotonergic medications have mood-altering effects by multiple convergent mechanisms:
Increasing serotonin production (eg, L-tryptophan, 5-HTP);
Inducing serotonin release (eg, amphetamines, cocaine, ecstasy);
Inhibiting serotonin metabolism (monoamine oxidase inhibitors, eg, tranylcypromine);
Inhibiting serotonin reuptake (serotonin reuptake inhibitors eg, fluoxetine; tricyclic antidepressants [TCAs] eg, amitriptyline, trazadone);
Stimulating serotonin receptors directly (eg, LSD).
They tend to be rapidly absorbed with narrow safety margins, so decontamination and activated charcoal are indicated in documented overdoses. Clinical signs are predominantly neurological, gastrointestinal and cardiovascular (Thomas and others 2012). Hyperthermia and disseminated intravascular coagulation (platelet activation is triggered by serotonin, in addition to hyperthermia) are possible.
Treatment of the neurological symptoms typically involves sedation and antagonism of serotonin using cyproheptadine (1.1 mg/kg orally or rectally in dogs). Autonomic instability can manifest as tachycardia and hypertension; if sedation and serotonin antagonism do not control this, β-blockers may be indicated.
More profound cardiovascular collapse including bradycardia with hypotension can be seen in TCA toxicity. IVLE therapy should be considered in cases refractory to traditional management.
Muscle relaxants (eg, baclofen)
Baclofen is a commonly prescribed muscle relaxant in people. It stimulates the GABA A receptor, hyperpolarising neuronal cell membranes and increasing inhibitory tone.
Cardiovascular manifestations of toxicity (alongside vomiting, sedation, respiratory arrest, coma and seizures) include hypotension, hypertension, bradycardia, tachycardia and conduction abnormalities. Bradycardia tends to be very responsive to atropine. Hypotension is managed with intravenous fluid therapy and vasopressor therapy. Hypertension of above 160–180 mmHg, particularly with evidence of target organ damage, would necessitate vasodilator treatment with sodium nitroprusside or amlodipine, for example. Amlodipine may be administered at the same dose per rectum, dissolved in water, where necessary (Geigy and others 2011). IVLE therapy has been reported to be of benefit and one dose of activated charcoal is likely to be sufficient due to a lack of enterohepatic circulation (Bates and others 2013, Behling-Kelly and Wakshlag 2018).
Although managing patients with neurological or cardiovascular intoxications can be challenging, a careful approach to the deranged physiology, with stabilisation of major body systems, can make these cases very rewarding to treat.
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