Lipid emulsion in the management of toxicity
Intravenous lipid emulsion is increasingly being used as an adjunct in the management of toxicity caused by lipophilic drugs that are cardiotoxic (e.g. bupivacaine) or neurotoxic (e.g. permethrin). The Veterinary Poisons Information Service recommends that intravenous lipid emulsion be considered for any animal at risk of serious toxicity after exposure to a lipophilic compound (VPIS 2017). This module summarises what is known about this treatment, the uncertainties, and the practical aspects of using it.
Lipid emulsions are sterile injectable products containing fatty acids in the form of fish, olive or soya oil, depending on the product. They also usually contain egg yolk phospholipids (as an emulsifier) and glycerol (to adjust tonicity) (Plumb’s Veterinary Drugs 2017). Lipid emulsions are used for parenteral nutrition as a source of calories and essential fatty acids in human and veterinary medicine. Other names for intravenous lipid emulsion include intravenous fat emulsion, intravenous triglyceride emulsion, lipid infusion and (when used in the management of toxicity) lipid rescue.
There are no licensed veterinary lipid emulsion products. Brands licensed for use in humans include Intralipid, Lipidem, Lipofundin and Omegaven. Product information for these brands is available on the Medicines and Healthcare Products Regulatory Authority website. They can be ordered through veterinary wholesalers or pharmacies; hospital pharmacies are also likely to keep them in stock. The shelf-life when new is 2 years and the products are stored at room temperature. They are available in various volumes (e.g. 100, 250 or 500mL) and are relatively inexpensive. For example, a 500 mL bag of 20% lipid emulsion costs less than £20. The product most commonly used in the management of toxicity is Intralipid 20%. A 250mL bag of Intralipid 20% is included in the ToxBox, a poisons management kit available via the Veterinary Poisons Information Service.
The mode of action of intravenous lipid emulsion in the management of toxicity is not completely understood. Studies suggest that lipophilic drugs are attracted away from tissues where they may cause harm, by the creation of an expanded lipid compartment in the blood – a so-called ‘sink’ effect (Fettiplace et al 2015; Bruenisholz et al 2012; Clarke et al 2011). Other possibilities are that lipids provide a source of energy to the tissues and, in the case of drugs such as bupivacaine, overcome inhibition of mitochondrial fatty acid metabolism (Fettiplace et al 2015) or reverse blockade of sodium channels (Wagner et al 2015).
There are very few clinical trials evaluating the efficacy and safety of intravenous lipid emulsion in the management of toxicity in humans or animals (Gosselin et al 2016). Clinical trials in this context are difficult to do because of variations in the dose of the toxic substance; patient characteristics; time delay before treatment; other treatments used; and because of ethical issues. However there are numerous experimental studies and case reports, many reporting apparent improvement in clinical status after administration of intravenous lipid. Case reports have inherent limitations: they are not controlled and so it is not possible to confidently attribute any effects to the intervention; and there may be biased reporting, with positive outcomes more likely to be reported than negative ones. In case reports and clinical trials, blood measurements of the toxin are often lacking and this can also limit interpretation of the results.
In human medicine, intravenous lipid emulsion is used in cases of serious systemic toxicity or cardiac arrest due to local anaesthetics, particularly bupivacaine. It is also used in cases involving certain other drugs when there is a high risk of death or organ damage and other accepted treatments have failed (Gosselin et al 2016; AAGB 2010).
Most of the published evidence on the use of intravenous lipid emulsion in animals is on the management of permethrin toxicity in cats. The evidence includes many case reports, but also a randomised controlled trial.
In the case reports, intravenous lipid emulsion was generally used as an adjunct to other therapies, including anticonvulsants, dexmedetomine, diazepam, methocarbamol, propofol, fluids, basic life support, and washing to remove permethrin from the skin. Cats received lipids by bolus injection plus infusion, or by repeated bolus (Muentener et al 2013; DeGroot; 2014; Ceccherini et al 2015). The authors reported reduced recovery and hospitalisation times, and some have suggested it may reduce the cost of treatment (Kuo & Odunayo 2013; Haworth & Smart 2012).
The randomised controlled trial involved 34 client-owned cats that had clinical signs of permethrin toxicity after direct application of a ‘spot on’ product intended for dogs (Peacock et al 2015). Cats that had diabetes mellitus, cardiac or renal disease or obesity were excluded. Toxicosis was assessed on a scale ranging from A (no clinical signs) to F (grand mal seizures). All cats were treated with methocarbamol (for tremor) and diazepam (for seizures) and were washed to remove permethrin from the skin (Peacock et al 2015). The cats were then randomised to receive an infusion of lipid emulsion 20% (the brand Ivelip, not available in the UK) or saline, at a rate of 0.25mL/kg/min for 60 minutes. Cats that received a lipid infusion improved more quickly: the mean time to achieve a clinical score of A or B was 5.5 hours (95% confidence interval [CI] 1.6 to 9.5 hours) compared with 16.2 hours with saline (95% CI 9.1 to 23.3 hours, p=0.006). However, the difference did not translate into shorter hospital stays; this may have been due to having to wait for owners to collect the cats. A bolus dose was not considered necessary in this study, but the trial’s authors suggested it might be beneficial in cases of cardiotoxicity, in which lipids may have a direct effect on the heart. An adverse effect was reported in one cat that received lipids: facial pruritus, which was successfully treated with chlorphenamine. The lack of measurement permethrin levels and of blinding (allowing the possibility of bias) limit interpretation of the results.
There are several case reports describing the successful use of intravenous lipid emulsion in the management of ivermectin toxicity in cats (Pritchard 2010; Kidwell et al 2014). One report described 20 cats that had been given an accidental 20-fold overdose of ivermectin by subcutaneous injection (Jourdan et al 2015). All the cats were given an intravenous bolus of lipid emulsion (1.5mL/kg) to prevent the onset of clinical signs of toxicity and four cats (which also had a low body condition score) also received a lipid infusion. None of the four cats that received a bolus plus infusion developed clinical signs, compared with 6 out of 16 of those that received a bolus alone. It is not possible to draw a robust conclusion from these cases. However, the report’s authors suggested that early intravenous lipid therapy (bolus plus infusion) should be part of the initial management of ivermectin toxicity in cats, particularly in those with a low body condition score that appear to be more at risk of toxicity.
Ivermectin and other macrocyclic lactones (milbemycin, moxidectin, selamectin) are substrates for P-glycoprotein, a protein involved in drug transport across cell membranes, which is thought to fulfil a protective effect, including restricting passage of drugs across the blood-brain barrier. Dogs with a mutation in the gene that encodes for P-glycoprotein – ABCB1 [previously MDR-1], are more susceptible to the neurologic adverse effects of macrocyclic lactones. The mutation primarily affects herding breeds of dog, particularly Collies and Australian Shepherds (standard and miniature) (Mealey et al 2008).
One case report of successful treatment with intravenous lipids involved a Collie dog with clinical signs of toxicity after ingestion of equine ivermectin paste. It received a bolus injection of lipids (1.5mL/kg over 10 minutes) followed by continuous infusion (0.25mL/kg/min for 60 minutes) in addition to supportive care and intravenous fluids. The dog received a second bolus and infusion of lipids 12 hours later and was discharged after 48 hours. The dog was later confirmed not to have the ABCB1 mutation (Clarke et al 2011).
Another report describes the treatment of three Australian shepherd dogs (two miniature) with severe neurologic signs of ivermectin toxicity and which had homozygous ABCB1 gene mutation (Wright et al 2011). The dogs received an intravenous bolus of lipid emulsion (1.5mL/kg) followed by infusion (0.25–0.5mL/kg/min over 30 minutes). Although all three dogs gradually recovered over several days, the authors concluded that intravenous lipid had no obvious benefit. The reasons for this are not known and the role of ABCB1 gene status unclear. The authors suggest the lack of effect may have been due to the dogs already having high brain tissue levels of ivermectin or a reduced ability to excrete ivermectin due to the defective P-glycoprotein, or because intravenous lipid was not used at an adequate dose. There is a report of successful treatment with intravenous lipid in a case of a dog with homozygous ABCB1 mutation with neurologic toxicosis due loperamide (which is also a substrate for P-glycoprotein) (Long et al 2017). The shorter elimination half-life of loperamide (around 11 hours) relative to ivermectin (2 days) may be a relevant factor.
In other published case reports, intravenous lipid emulsion has been used with apparent success in the management of toxicity due to baclofen (Khorzad et al 2012; Bates et al 2013), diltiazem (Maton et al 2013), lidocaine (O’Brien et al 2010), loperamide (Long et al 2017), milbemycin (VPIS case 181681), moxidectin (Crandell & Weinberg 2009; Bates et al 2013) and synthetic cannabinoids (Williams et al 2015). There are also reports of its use in the management of plant poisoning (Bischoff et al 2014) and tremorgenic mycotoxins from mouldy material (Parratt 2014).
Intravenous lipid emulsions should not be used in patients with severe disorders of fat metabolism and used with caution in patients with impaired fat metabolism (e.g. diabetes mellitus, pancreatitis) (Intralipid 20% SPC). The products should not be used in animals with known allergy to ingredients (e.g. egg, fish).
Intravenous lipid emulsion can be used in young (including neonatal) and elderly patients and has been used safely during human pregnancy (Intralipid 20% SPC). Plumb’s Veterinary Drugs recommends using lipids with caution in neonates because of an increased risk of lipid emboli.
Intravenous lipids may interfere with laboratory measurements if blood is sampled before the lipid has been adequately cleared from the bloodstream (generally stated to be 5 to 6 hours in humans). It is therefore important to take blood for tests before administration of the lipid and be aware of possible interference when interpreting blood results. In theory, intravenous lipid may also reduce the effects of concurrent lipophilic drug treatments.
Adverse effects from the use of intravenous lipid emulsion in the management of toxicity appear to be rare but are probably under-reported. In veterinary cases, reported effects include pancreatitis (Gwaltney-Brant and Meadows 2012; VPIS data), hyperlipidaemia (Gwaltney-Brant and Meadows 2012, Maton et al 2013), unilateral facial pruritus (Peacock et al 2015), extravasation with pain and local swelling (Bates et al, 2013), gross lipaemia lasting more than 48 hours, and suspected corneal lipidosis (Seitz and Burkitt-Creedon 2016). In humans, reported effects include respiratory complications (ranging from hypoxia to respiratory failure), fat embolism and fat overload syndrome (Hayes et al 2016). Adult respiratory distress syndrome is often a complication in critically-ill poisoned patients, particularly those who develop cardiac arrest, so it is not clear if respiratory complications are directly caused by the lipid (Hayes et al. 2016). Hypersensitivity reactions are also a potential risk.
The optimal dosing regimen for intravenous lipid emulsion in the management of toxicity is not known. The typical regimen is an intravenous bolus of a 20% lipid emulsion (1.5 mL/kg) followed by an infusion (0.25 mL/kg/minute) over 30–60 minutes. This can be repeated once or twice if signs of toxicity recur; if there is no response it can be discontinued.
Before repeating a dose, a peripheral blood sample should be checked for evidence of lipaemia and no further doses given if serum is grossly cloudy (i.e. appears milky). The volume of lipid infused over a short period can result in fluid overload but, if this is a concern, other fluids can be stopped temporarily or the infusion rate reduced.
Lipid emulsion should not be mixed with other liquids, and should be given via a separate intravenous catheter. It is important to use an aseptic technique while handling lipid emulsions because they are a good growth medium for microorganisms. The product information (summaries of product characteristics [SPCs]) recommends that any unused product should is discarded.
Intravenous administration of lipid emulsion is an option for use as an adjunct in the management of toxicity due to fat soluble (lipophilic) drugs. It is a simple and relatively inexpensive treatment, but is not licensed for this use in animals.
Evidence on the use of intravenous lipid emulsion in veterinary medicine is sparse. Most published evidence is on permethrin and ivermectin toxicity. One randomised controlled trial in cats with permethrin toxicity indicates that intravenous lipid speeds recovery but whether it reduces hospitalisation and the cost of treatment is unproven. Evidence from case reports only suggest that lipid emulsion might have prevented the development of clinical signs in cats at risk of ivermectin toxicity; in dogs with ivermectin toxicity it appeared to aid recovery in some, but appeared unhelpful in some cases of severe toxicity.
Much remains unknown about intravenous lipid in the management of toxicity, including the optimal timing of administration, optimal dose for different drugs and toxins, when to stop therapy, adverse effects, and interaction of lipid with other treatments.
Intravenous lipid emulsion is not a substitute for standard supportive and symptomatic care and there is currently insufficient evidence to support its routine use in veterinary practice. However it is worth considering in animals with signs of severe toxicity. Advice on individual cases and information on whether intravenous lipid emulsion has been used in previous cases of toxicity with particular substances is available from the Veterinary Poisons Information Service.
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Our modules start with a detailed outline and electronic literature search. We commission a collaborating author, who is a specialist in the module topic, to write a draft module. The collaborating author on this module was Nicola Bates. The draft is circulated unsigned to a wide range of commentators, include practising first-opinion vets, other topic specialists, the companies that market any mentioned drugs and other organisations and individuals, as appropriate. They can raise points about the interpretation of evidence, ask questions that are important to clinical practice, and present alternative viewpoints. There is a rigorous editing and checking process and the result is a module that is evidence-based, impartial and relevant to clinical practice. The final module is unsigned because it is the result of collaboration. References
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