Lipid Rescue: a Novel Antidote?

Dr. Wilco Botha, BSc BVSc – Small Animal Internal Medicine Resident

Faculty of Veterinary Science, University of Pretoria.

Intravenous lipid emulsion has been utilised as the fat component of parenteral nutrition and as a vehicle for drug delivery in drugs such as propofol for over half a century. More recently it has gained acceptance in the treatment of lipid soluble (lipophilic) drug toxicities.

Intravenous lipid emulsion has been utilised as the fat component of parenteral nutrition and as a vehicle for drug delivery in drugs such as propofol for over half a century. More recently it has gained acceptance in the treatment of lipid soluble (lipophilic) drug toxicities.

The potential benefits of intravenous lipid emulsion therapy (ILET) in altering toxicokinetics were discovered in the 1980’s when researchers noted its effect on lipophilic drugs such as cyclosporine in rabbits. Ever since, the value of ILET on various lipophilic drug toxicosis has been experimentally evaluated and eventually utilised in the emergency room.

In 2009 the first successful treatment of moxidectin induced toxicosis in a puppy in clinical veterinary medicine was published. Presently, in human medicine, ILET is reserved for life-threatening, severe toxicosis or for when conventional antidotes or resuscitation therapies have failed. In veterinary medicine the approach differs slightly in that ILET is often instituted earlier in the management of toxicities. The successful use of ILET in clinical toxicology has been reported in numerous case reports and case series. In veterinary medicine the successful treatment of macrocyclic lactone, local anaesthetic, calcium channel blocker, beta-blocker, central-acting muscle relaxant and insecticide toxicosis have been described.

The exact mechanism of action of ILET is unknown but four hypotheses have been proposed. The most widely accepted hypothesis is thought to be that ILET acts by creating a new intravenous lipid compartment (“lipid sink phenomenon”) which functions to trap and hold the lipophilic toxicant, leaving less active toxicant available to effector tissues causing clinical effects of toxicity. Additional possible hypotheses have been described with specific reference to local anaesthetic systemic toxicosis for which it was initially most commonly used for in human medicine. For more detail see Cave et al. The latest studies, however, suggest that ILET functions by acting as a vehicle for the toxicant, drawing the toxin from highly perfused effector organs such as the brain, liver and heart into the aqueous phase and now extended lipid phase,and transporting the toxin to tissues of poorer perfusion. ILET has been reported to shorten the excretion time and lower the LD 50 of lipophilic drugs supporting the latest hypothesis.

ILET is generally considered a safe treatment for appropriate cases. The use of ILET should be reserved for severe toxicoses with a high mortality rate where there is no established antidote or where the established antidote or supportive therapy is cost prohibitive such as when mechanical ventilation is required. Additionally, the toxicant should be known to be adequately lipid soluble. The lipid solubility or lipophilicity of a drug is expressed as a partition coefficient value designated as the Log P value. A toxicant with a Log P value greater than one is considered lipophilic. However, the solubility of toxicants is also dependent on factors such as the acid-base balance of the patient due to pH ionisation effect, patient temperature and haemodynamic stability of the patient. These factors should be corrected prior to ILET. ILET is only suitable for toxicants with short to moderate half-lives and not suitable in long-lived toxicosis with for example rodenticides (anticoagulant and vitamin D compounds) Lipid emulsions, as all parenteral nutrition components, are ideal growth mediums for microbes. If ILET is considered in a patient the practice should be equipped to allow for aseptic infusion practice, intensive monitoring during therapy and allow for precise dose and rate administration using a drip pump.

The use of ILET is off-label and considered experimental which should be carefully explained to and approved by the owner. The recommended dosage guidelines in veterinary medicine were extrapolated from that recommended in human medicine. In a review evaluating all the published literature and dosage recommendations in human medicine Fernandez et al. proposed a bolus administration of a 20% intravenous lipid emulsion (Intralipid. 20%, Fresenius Kabi is most commonly used)at 1.5ml/kg over 1 minute followed by a constant rate infusion of 0.25ml/kg/min for 30 to 60 minutes. If no improvement is noted ILET is unlikely to work and must be discontinued. If some improvement is noted but some clinical signs persist intermittent boluses of 1.5ml/kg may be repeated at 4 – 6 hourly intervals for 24 hours and to a maximum of 8ml/kg/day. Alternatively, a constant rate infusion of 0.5ml/kg/hour for up to 24 hours is presumed to be reasonably safe.

Reported side effects with the use of ILET in veterinary cases include post-infusion facial pruritus in a cat responsive to chlorpheniramine. Pancreatitis and hyperlipidaemia are the most common side effects reported to the American Animal Poison Control Center due to the use of lipid emulsions secondary to hyperlipidaemia. A single report of extravasation injury causing local pain and swelling has also been described. The side effects, of ILET secondary to microbial contamination when used as part of a parenteral nutrition protocol are well described, however patients requiring parenteral nutritional are more compromised than healthy animals presenting with acute toxicity.

Most commercial lipid emulsion preparations are stabile at room temperature for up to 2 years but once opened need to be used within 24 hours or discarded and replaced every 24 hours. Appropriate product storage and strict aseptic technique during the ILET is imperative to prevent contamination.

Side effects described in human medicine can be grouped as directs effects including colloidal changes, pyrexia or anaphylaxis. These are rare with anaphylaxis reported in < 1% of humans and usually manifests within 20 minutes of administration. Fatty overload syndrome (FOS) is seen when an excess amount of lipid emulsion is administered. In humans FOS is seen at rates over 0.11g/kg/day. Clinical signs include fat embolism, hyperlipidaemia, hepatomegaly, icterus, splenomegaly, thrombocytopaenia, prolonged clotting times, haemolysis and neurological signs. These side effects are thought uncommon when using ILET in clinical toxicology due to the difference in administration technique. In toxicosis large boluses and infusions are given over short periods but the total daily dose is significantly less than that administered during parenteral nutrition. ILET should be avoided in patients that are critically ill patients or those suffering from severe pulmonary disease or sepsis as in humans it caused worsening of oxygenation and diffusion parameters on arterial blood gas measurement.

In conclusion, ILET is a life-saving, non-specific treatment for a variety of lipophilic toxicities causing a rapid and dramatic improvement in clinical signs with decreased hospitalisation time. However, it does not replace conventional antidote therapy and supportive care. Commercial lipid emulsions are relatively inexpensive with a long shelf-life and easy to administer. Although the treatment is off-label and experimental, acceptance for its clinical use has grown, and continues to do so. Further research to elucidate on its safety and efficacy in clinical toxicology is needed. Appropriate case selection, understanding the mechanism of action of both ILET and toxicant, as well as sufficient resources in a hospital setting to allow for careful monitoring and exact administration technique is imperative for a successful outcome.

List of toxicants whose side effects may potentially be reversed with the use of intravenous lipid emulsion therapy:

Toxicant : Log-P value

  • Amlodipine* 1.90
  • Baclofen* 1.30
  • Carprofen* 4.13
  • Chlorpheniramine* 3.17
  • Chlorpromazine* 5.35
  • Clomipramine* 3.30
  • Cyclosporine* 3.00
  • Dexamethasone* 1.83
  • Diazepam* 2.82
  • Digoxin* 1.26
  • Diltiazem* 2.80
  • Ibuprofen Δ 3.50
  • Itraconazole* 5.90
  • Ivermectin* 3.50
  • Ketoprofen* 3.12
  • Lidocaine* 2.26
  • Moxidectin* 4.10
  • Permethrin Ŧ 6.10
  • Promethazine* 2.85
  • Vinblastine* 3.69

* Fernandez et al., 2011 Δ Bolfer et al., 2014 Ŧ Peacock et al., 2015

Checklist for the successful use of intravenous lipid emulsion therapy:

• What is the lipophilicity (published Log-P value) of the toxicant?

• Is there an established, effective antidote available for the toxicant?

• Is the toxicosis severe enough to require nonstandard intervention?

• Is the present standard of care or antidote therapy cost prohibitive?

• Does the owner understand the experimental nature of the therapy, the possible side effects and consent to its

off-label usage?

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