Lipid infusion can be used in the management of poisoning with fat soluble (lipophilic) substances. It is also known as lipid rescue, intravenous fat emulsion and intravenous lipid emulsion (IVLE) and was first proposed by Weinberg in 2006 as a treatment for the management of severe local anaesthetic toxicity in humans (Weinberg, 2006).
What is it?
Lipid infusion therapy is the intravenous infusion of a parenteral lipid formulation which is usually used as part of parenteral nutrition as a source of calories and essential fatty acids. The lipid used is commonly soy bean oil in water. The most commonly used product is Intralipid® 20% (Fresenius Kabi), but other products are available. Intralipid®, for example, contains soy bean oil, egg yolk phospholipids, glycerin and water for injection.
How does it work?
In simplest terms the lipid acts as a ‘shuttle’ where the toxic chemical is redistributed away from target sites. The lipophilic drug or chemical dissolves in the lipid emulsion with accelerated removal of the toxic molecules from target tissues (Fettiplace et al, 2015a). There is some support for the lipid ‘shuttle’ theory. In experimental studies a higher concentration of a toxic agent was found in the lipid phase of the blood in rats compared with the aqueous (water) phase for several drugs (Krieglstein et al, 1974; Straathof et al, 1984; Weinberg et al, 1998), suggesting that the drugs were sequestered in the lipid. In clinical cases involving ivermectin toxicity the blood concentration of ivermectin in a Shetland pony (Bruenisholz et al, 2012) and a Border collie (Clarke et al, 2011) increased substantially after administration of the lipid, suggesting that the drug moved into the blood from other compartments.
Lipid infusion may also have a metabolic effect in some circumstances, for example providing a source of energy to myocardial cells which may be relevant for drugs that cause toxic cardiac effects (Fettiplace et al, 2015a). In addition, in experimental studies with bupivacaine-induced cardiac toxicity, cardiac output was shown to improve with lipid therapy not only due to decreased tissue concentrations of the local anaesthetic drug, but also by a direct effect of the lipid emulsion on the force of contraction (Fettiplace et al, 2015a).
The mechanism of action of lipid infusion is not fully understood. Lipid infusion also appears to be effective for some drugs which are not lipophilic, such as the muscle relaxant baclofen, so there must be some other mechanism operating in these cases. In addition lipid has been ineffective in some cases (Wright et al, 2011) and the reasons for this have not been fully elucidated.
What poisons has it been used for?
In veterinary medicine lipid infusion is used for a number of drugs including local anaesthetics such as bupivacaine (O'Brien et al, 2010), baclofen (Bates et al, 2013; Edwards et al, 2014), diltiazem (Maton et al, 2013) and macrocyclic lactones such as ivermectin (Pritchard, 2010; Clarke et al, 2011; Bruenisholz et al, 2012; Kidwell et al, 2014; Jourdan et al, 2015; Saqib et al, 2015) and moxidectin (Gwaltney-Brant and Dunayer, 2008; Crandall and Weinberg, 2009). It is used in the management of poisoning with the insecticide permethrin (Brückner and Schwedes, 2012; Haworth and Smart, 2012; Kuo and Odunayo, 2013; Muentener et al, 2013; DeGroot, 2014; Ceccherini et al, 2015, Seitz and Burkitt-Creedon, 2016) and has been used in the management of plant poisoning (Bischoff et al, 2014), tremorgenic mycotoxins from mouldy grain or food products (Parratt, 2014) and suspected synthetic cannabinoid (a so called ‘legal high’) poisoning (Williams et al, 2015).
What animals has it been used in?
Most veterinary cases where lipid infusion has been used in the management of poisoning involve cats and dogs, but it has been used in other species including goats (Bischoff et al, 2014), a pony (Bruenisholz et al, 2012) and even an African lion (Saqib et al, 2015).
What is the evidence for lipid infusion in poisoning?
Although there are numerous experimental studies and case reports in humans and animals that report improvement in clinical status after administration of intravenous lipid, there are very few clinical trials evaluating the efficacy or safety of lipid infusion in acutely poisoned humans or animals.
Clinical trials in subjects with poisoning are an issue because the dose of the toxic substance may be different in the various cases, and there are also variations in patient characteristics, time to treatment and treatments used. In case reports and clinical trials blood measurements of the toxin are often lacking which can limit interpretation of the results. Also it is sometimes difficult in case reports to attribute the improvement to lipid alone as the patients have usually received multiple interventions and therapies.
In a clinical trial of lipid infusion in the management of permethrin-poisoned cats the clinical signs were scored from asymptomatic to grand mal seizures. Cats admitted to the hospital for permethrin toxicity were randomised to receive lipid or saline, but other drugs such as methocarbamol and diazepam were also permitted. Cats given lipid had more rapid reversal of severe clinical signs and less morbidity than cats that did not receive lipid. Both these findings were statistically significant. Permethrin was not measured in blood (Peacock et al, 2015).
In 20 cats given an accidental 20-fold overdose of ivermectin by subcutaneous injection, the decision was made to treat some with a bolus dose and then an infusion of lipid and others were given only a single bolus dose of lipid. The six cats that subsequently developed signs had all received only a single dose of lipid. Also animals with a low body condition score were also more likely to develop toxic effects. There were no measurements of ivermectin in blood samples in this case series (Jourdan et al, 2015).
Availability and cost
Lipids are used as a component of parenteral nutrition in human medicine. They are readily available from most hospital pharmacies (depending on whether the hospital is able to dispense drugs to a veterinary practice in an emergency) and veterinary wholesalers.
Lipid does not require refrigeration until opening and the shelf-life (depending on the product) is about 24 months. It is available in various size bags (e.g. 100, 250 or 500 ml) and concentrations of lipid (10, 20 or 30%) and is inexpensive (Cormier and Gosselin, 2016); a 500 ml bag of 20% lipid (the recommended concentration), for example, is less than £20.
What are the risks?
Adverse effects from the use of lipid infusion in the management of poisoning appear to be rare but may be under reported.
Adverse effects reported in veterinary cases include pancreatitis (Gwaltney-Brant and Meadows, 2012), 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) and prolonged gross lipaemia (lasting more than 48 hours) and suspected corneal lipidosis (Seitz and Burkitt-Creedon, 2016).
Respiratory complications (ranging from hypoxia to respiratory failure), fat embolism and fat overload syndrome have been reported in humans treated with lipid infusion (Hayes et al, 2016). Adult respiratory distress syndrome (ARDS) is often a complication of critically-ill poisoned patients, particularly those that 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.
There is also the potential for delayed toxicity as the toxin diffuses out of the lipid or as the lipid is metabolised. The disposition of the drug or toxin after lipid infusion is unknown (Weinberg, 2012); there are no studies investigating this issue. Recurrence of toxicity has been reported following cessation of lipid administration in human cases (Marwick et al, 2009; McAllister et al, 2012). In a veterinary case series involving 20 asymptomatic cats, some cats given only a bolus dose developed signs of ivermectin toxicosis whereas all the cats given a single bolus followed by lipid infusion remained asymptomatic (Jourdan et al, 2015).
Experimental animal studies have suggested an adverse outcome of resuscitation and lipid infusion in the presence of hypoxia (Mayr et al, 2008; Harvey et al, 2009) and this may be due to changes in the binding capacity of the lipid.
Contraindications
Lipid should not be given to animals with disorders of fat metabolism, liver disease or pancreatitis. Some products contain egg-yolk phospholipids as emulsifiers so should not be used in animals with egg allergies.
Interference with laboratory analyses
Lipids in blood may interfere with some laboratory measurements (Nikolac, 2014; Grunbaum et al, 2016) such as bilirubin, lactate dehydrogenase, oxygen saturation, haemoglobin, if blood is sampled before the lipid has been adequately cleared from the bloodstream (this is generally stated as 5 to 6 hours in humans). This interference can be due to physical and chemical interference, particularly for electrophoretic testing methods, non-specific interference in immunoassays and most commonly interference in spectrophotometric testing methods as lipid particles can absorb light. Other potential causes include volume depletion and excipients (inactive substances and carriers) in the lipid emulsion which can interfere with the test. It is therefore important to take blood for tests prior to administration of lipid and be aware of possible interference when interpreting blood results.
How do you know a substance is lipophilic?
The lipophilicity of a chemical is described by a particular physiochemical property — the partition coefficient, which is known as the log P. In technical terms the log P is the ratio of concentrations of a compound in a mixture of two immiscible (non-mixing) liquids at equilibrium. It is therefore a measure of the difference in solubility of the compound in these two liquids. A lipid soluble compound has a high log P (>1) and a water soluble compound has a low log P (<1). For example permethrin has a log P of 6.5, whereas the herbicide glyphosate has a log P of -4.6 (Table 1).
Table 1. Examples of the log P of various compounds
| Compounds | Log P |
|---|---|
| Bupivacaine | 3.4 |
| Ivermectin | 4.1 |
| Moxidectin | 4.3 |
| Penitrem A (a tremorgenic mycotoxin) | 3.8 |
| Permethrin | 6.5 |
| Roquefortine (a tremorgenic mycotoxin) | 3.0 |
Another factor to consider is a compound's volume of distribution. This is the measure of the distribution of a substance between plasma and the rest of the body after oral or parenteral administration. Lipophilic substances are able to penetrate more cellular barriers because of their lipophilic nature and hence distribute into a larger volume of tissue fluid. Therefore, substances with a larger volume of distribution are more likely to have lipophilic characteristics that allow them to dissolve into lipid emulsions.
In addition, lipid infusion is only suitable for lipophilic compounds with short to moderate half-lives; it is not suitable for lipophilic compounds with longlives such as vitamin D compounds (e.g. calciferol, calcipotriol) and anticoagulant rodenticides (e.g. brodifacoum, bromadiolone). Chronic infusions of lipid for a prolonged period (e.g. for hours over a period of days) are not recommended as this could result in lipid overload (Weinberg, 2011).
There are numerous sources that provide information on the physico-chemical properties of chemicals, including the log P (sometimes given as XLogP3). These resources include PubChem Compound (www.ncbi.nlm.nih.gov/pccompound/) and Drug Bank (www.drugbank.ca/drugs/).
When is it used?
Administration of lipid infusion in human medicine is generally used when severe signs have occurred or when other therapies have failed, but it is sometimes used much earlier in the course of poisoning in veterinary medicine, sometimes even before the onset of clinical signs in an animal at risk of severe toxicity (e.g. Jourdan et al, 2015). While this may indicate a more cautious approach in human medicine and an insistence on evidence from randomised clinical trials, it also reflects the greater access to intensive care in human medicine.
Lipid infusion should be used in animals with signs of severe poisoning that fail to respond to other therapies. It would not be recommended routinely in animals without clinical signs of toxicosis, but if the history suggests risk of severe poisoning (e.g. exposure to a potentially lethal dose) then lipid should be available for administration if required.
What is the dose?
The optimal dosing regimen is unknown. There is no standard regimen for lipid infusion but it is generally given as an intravenous bolus followed by an infusion (Figure 1). This bolus/infusion regimen is recommended (Fernandez et al, 2011) because there are occasional reports of recurrence of toxicity following cessation of lipid administration or where only a bolus dose has been given.
Administration of lipid infusion should ideally be followed by monitoring of vital signs (pulse, blood pressure, respiratory rate and oxygen saturation) and electrocardiogram (ECG). Amylase concentrations should be measured if there is clinical evidence of pancreatitis.
How is lipid given?
The lipid is given via a separate intravenous catheter (Figure 2) and is not mixed with other liquids. It is important to use aseptic techniques as the lipid provides a good growth medium for microorganisms. Any unused lipid should be stored in the refrigerator but must be discarded after 24 hours.
What about giving other lipophilic drugs?
Administration of lipids in animals receiving therapy with lipophilic drugs such as propofol has been raised as a potential concern; however the use of lipid is expected to reduce the need for such emergency therapy. The potential effect of lipid infusion on concentrations of other therapeutic agents including antidotes should be assessed on an individual case basis. In addition, only a small quantity of lipid crosses the blood brain barrier and for propofol, at least, the effect of lipid on propofol-induced sedation is expected to be low (Gragasin et al, 2009).
Conclusion
Intravenous infusion of lipids is a potentially lifesaving option in the management of poisoning for certain substances, particularly permethrin and ivermectin. It is a simple, easy to administer and cheap treatment that is becoming increasingly used as an adjunct to conventional treatments in the management of toxicity caused by lipophilic and cardiotoxic compounds. It should be considered in an animal with clinical signs of severe poisoning after exposure to a lipophilic, and some other, compounds. Much, however, remains unknown. For advice on an individual case contact a poisons information service.
Key Points
- Administration of an intravenous lipid preparation can be used in the management of some poisoning by some substances, particularly fat soluble compounds.
- The mechanism of action is not fully understand but may, in part, involve ‘shuttle’ resulting in redistribution of the toxic drug or compound.
- Lipid infusion should be considered in any animal failing to response to conventional therapies, if they have been exposed to a suitable lipophilic compound.
- Lipid should not be given to any animal with disorders of fat metabolism, liver disease or pancreatitis.
- Although numerous cases are reported in the human and veterinary medical literature there is still a lot to learn about the place of lipid infusion in the management of poisoning.
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