Vet360, December 2016 - Page 24

TOXICOLOGY 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 vet360 Issue 06 | DECEMBER 2016 | 24 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