Philip R Judge BVSc MVS PG Cert Vet Stud MACVSc (Vet. Emergency and Critical Care; Medicine of Dogs)
Introduction
The first report of the use of intravenous lipid emulsion (ILE) therapy was in 2006, in a human experiencing cardiac arrest secondary to bupivacaine toxicosis1. Since that time, ILE therapy has been utilized in a wide range of toxicosis. The direct impact of ILE in management of toxicosis is at time, unclear, as published case reports usually only reflect positive outcomes, and the independent impact of ILE is difficult to prove in a patient receiving concurrent therapies as part of their illness management1,2.
The aim of this short review is to examine the scientific data on ILE in the management of toxicosis in dogs and cats, and to outline sound recommendations on its use, based on available understanding.
Mechanism of Action:
Broadly, the effects that ILE infusion has on toxicosis include either scavenging or non-scavenging mechanisms of action1-4.
Scavenging mechanism:
Following intravenous administration of ILE, the high lipid concentration within the plasma scavenges xenobiotic (foreign chemicals) molecules from target tissues, including the heart, muscles, CNS etc., and shuttles them to tissues where they are either stored (skeletal muscle, adipose tissue); metabolised (liver) or excreted (kidney).
Lipid solubility, as well as the degree of xenobiotic ionization appear to be the most important factors in determining the effectiveness of the lipid shuttle scavenging system.
Non-scavenging mechanism:
Non-scavenging mechanisms of ILE activity are numerous and include blood pressure maintenance via alteration in nitric oxide signaling, direct cardiotonic effects, and a post-conditioning effect that minimises reperfusion injury1.
Other documented non-scavenging mechanisms studied in bupivacaine toxicity include
- Calcium-mediated positive inotropism theory2
- Because fatty acids can increase calcium concentrations in cardiac myocytes, lipids may cause an increase in inotropy that overcomes the cardiac depressive effects of certain intoxications e.g. calcium-channel toxicities
- Free fatty acid energy theory2
- Myocardial cells obtain 80-90% of their energy from free fatty acids
- Intravenous lipid overwhelms bupivacaine inhibition of carnitine exchange, and augments mitochondrial fatty acid metabolism, increasing ATP stores and myocardial energy available for cardiac myocytes to recover from myocardial depressant effects of local anaesthetic toxicity.
Formulation:
20% lipid emulsion (Intralipid) is recommended. 30# lipid emulsions are available and may be preferred in severe cardiotoxicity in cases of local anaesthesia toxicity1.
Dosage:
Note that the following dosing regimes are stated using 20% lipid emulsion formulations1,2,28.
- Doses published in literature vary, and are largely based on case reports and case series, with no controls or dose variation to assess minimum effective doses.
- The most widely published doses in veterinary medicine are:
- Initial bolus: 1.5 ml/kg given IV over 2-3 minutes, PLUS
- Continuous infusion of 0.066-0.25 ml/kg IV for 60 minutes
- Other doses, extrapolated from human medicine, are more conservative in dose, and are outlined below. These doses are associated with variable effectiveness in both dogs and cats:
- Bolus: 1.5 ml/kg IV over 2-3 minutes PLUS
- Continuous infusion of 0.25 ml/kg/minute for 3 minutes only, followed by
- Continuous infusion of 0.025 ml/kg/min for up to 6.5 hrs
- Repeat doses:
- Repeated doses may be indicated in patients showing initial response to therapy, but showing recurrence of clinical signs associated with toxicity
- Blood test at 4-6 hrs. following completion of continuous infusion.
- If no lipaemia is observed, and the patient is still clinically unwell because of toxicosis, the bolus and/or the infusion dose may be repeated
- If lipaemia present, withhold treatment; retest for lipaemia q 2 hrs.
- Repeat dose only if lipaemia has resolved
- Maximum dose:
- The maximum dose limit for ILE has not been established in dogs and cats
- In humans, the maximum dose per 24 hr period is established at 8-10 ml/kg/24hrs
- A recent retrospective study in dogs and cats showed adverse reactions to ILE increased when the dose exceeded 12 ml/kg (dogs) and 14 ml/kg (cats) – although adverse effects were seen at doses as low as 2 ml/kg
Clinical Uses:
Numerous case reports, case series, and a few clinical trials have been published in recent years, evaluating the response to administration of ILE in a range of toxicosis5. A brief summary of these is provided in the table below:
| Toxicant | Response to Therapy | Additional Recommendations |
|---|---|---|
| Amlodipine6 | Variable response | Adjunctive therapy recommendation only |
| Amphetamine/methamphetamines6,7 | Moderate response | Useful adjunctive therapy |
| Baclofen8 | Good response. May require multiple doses | Recommended for most cases, particularly those with severe symptoms |
| Bromethalin6,9 | Variable response from poor to good | Adjunctive therapy recommendation only |
| Carprofen10 | Good response | Potentially beneficial as adjunctive therapy |
| Cocaine11 | Good response | Potentially beneficial as adjunctive therapy |
| Diltiazem12 | Good response when combined with high dose insulin (canine case report) | May be useful in severely affected patients |
| Ibuprofen13 | Improvement in neurological status | Useful especially if neurological signs present |
| Lidocaine, bupivacaine14 | Good response | Recommended for cases with CNS or cardiovascular symptoms |
| Loperamide15 | Positive response | Use naloxone initially; second line treatment with ILE only in refractory cases |
| Macrocyclic lactones (ivermectin, milbemycin, moxidectin etc.)1,2,16-21 | Good response observed; poor response in dogs with ABCB1-delta mutation | Useful treatment. Dogs with ABCB1-delta gene mutations may not respond |
| Marijuana22 | Good response | Use for severely affected patients is likely justified; mild symptoms probably don’t require ILE |
| Naproxen23 | Insufficient data | Insufficient data to recommend |
| Organophosphates1,5 | Poor response | No evidence to support use of ILE at this time |
| Permethrins24-26 | Moderate to good improvement in most cases | Adjunctive therapy recommendation |
| Phenobarbital1,2 | Mild to moderate response | Consider in severely affected patients |
| Tremorgenic mycotoxins27 | 96% positive response | Consider in severely affected patients refractory to methocarbamol and benzodiazepines |
Precautions and Adverse Reactions1,2
Side effect and adverse reactions to ILE therapy are infrequent but have been reported. A summary of reported adverse effects is listed below:
- Anaphylactoid reaction
- Bacterial contamination of solution
- Sterile preparation and administration technique should be used
- Discard unused solutions after 24 hrs.
- Pulmonary lipid emboli
- Reported in human paediatric patients receiving ILE therapy
- Lipaemia
- If lipaemia is present in blood tests following treatment, subsequent doses should be delayed until serum is non-lipaemic, recommended to ostensibly reduce risk of pancreatitis that has been observed in humans and veterinary patients following ILE therapy
- Poor response to treatment
- Do not administer more than 3 doses if no significant response is seen
- Non-selective binding of therapeutic agents
- ILE may bind to antidotes or supportive medications e.g. benzodiazepine medications used to control seizures, and may worsen symptoms of toxicity as a result
- Discontinue use if deterioration of patient status is observed
- Reappearance of clinical signs
- Most notably in toxicosis caused by agents with long half-lives. Repeated ILE infusions may be required in such cases
- Immune compromise in septic patients
- Volume overload (especially with repeated doses)
- Fat over load syndrome
- Due to excessive volumes or high administration rates, or administered to patients with reduced lipid clearance rates (liver disease etc.)
- Leads to
- Hyperlipidaemia
- Fat embolism – lungs, brain
- Hepatomegaly
- Icterus
- Splenomegaly
- Thrombocytopaenia
- Increased clotting times
- Haemolysis
Pharmacodynamics and Excretion4:
ILE has the following clearance properties from circulation:
- Skeletal muscle: 47%
- Splanchnic viscera: 25%
- Myocardium: 14%
- Subcutaneous tissues: 13%
Conclusion:
The use of ILE in small animal toxicology has led to improved clinical outcomes in a wide range of toxicities, including from compounds with both highly lipophilic properties, to those that are less lipophilic as well. Evidence to date involves mostly small cohorts of patients, or case reports, however, which does give rise to equivocal or uncertain recommendations for some of these agents. The hope is for more prospective control-based studies in future, so that our knowledge of the effects of ILE on various toxicities becomes more objective. In the meantime, it appears that ILE is a reasonably safe, useful adjunctive therapy to consider where we have published evidence of efficacy to date.
References:
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