I was so happy you saved his life I did the crazy happy dance.
The use of intralipid therapy has been gaining traction as a treatment option for an ever expanding range of toxicities. While it has not quite become the standard of care, it has been viable for patients in the veterinary field and has been reported as case studies in the human field.
Veterinary literature has reviewed intravenous lipid emulsion therapy (ILE) [1,2] and published case reports or studies are available noting efficacy in toxicities including macrocyclic lactones [3,4], baclofen , beta-blockers, calcium channel blockers , NSAID [7,8], bromethalin , lidocaine , permethrin toxicity [11,12], tricyclic antidepressants (13). Intravenous lipid emulsion (ILE) in human literature has been reported as a therapy for local anesthetic [14,15] calcium channel blocker [16,17], psychotropic medication  , glyphosatesurfactant herbicide toxicities and even cocaine overdosage . Original work performed by Weinberg noted a response in rats with bupivicaine induced systole with lipid emulsion . How exactly ILE works is not certain but two theories are considered. The “lipid sink” theory is most commonly considered the primary mode of action. In this theory, the formation of a lipid compartment within the intravascular space can serve as a “sink” into which the lipophilic drug will be drawn into. The drug is then excreted/metabolized. Determination of a drug’s lipophilicity may be noted by its log P value. A value >1 indicates lipophilic compound which may move into the temporary lipid phase and be less distributed throughout the body. The formulation of ILE utilized may play a role and supports the “lipid-sink” theory based on one study . This theory has been supported in two case reports that followed plasma ropivacaine  and serum verapamil concentrations . An alternate theory is that the lipid provides an energy source for the cardiac myocytes by increasing the availability of FFA. The increase of FFA may also aid in increasing the activation of voltage-gated calcium channels in the myocardium, increasing cytosolic calcium channels This mechanism may be most important in cases of calcium-channel blockade [23,24].
There has not been an absolute protocol established for administration of intralipid therapy. A commonly utilized protocol includes an IV bolus of 20% ILE (1.5 mL/kg) followed by a continuous rate infusion of 0.25 mL/kg/min for 30–60 minutes. IntraLipid 20% (Baxter) is the most commonly referred to solution. It is composed 20% Soybean Oil, 1.2% Egg Yolk Phospholipids, 2.25% Glycerin, and Water for Injection. It may be infused through a peripheral intravenous catheter (350 mOsmol/kg water) without the use of a filter. The solution must be handled aseptically. Complications of ILE therapy may include fever, hyperlipemia, thrombocytopenia, hemolysis, prolonged coagulation times, seizures or anaphylactoid reactions to the soybean component. In one cat corneal lipidosis was suspected following treatment for ivermectin toxicity . The ph of Intralipid may vary from 6-9 pending where it is is in its shelflife which should be taken into account in the individual patient. While the log P value predicts the lipophilicity of a drug, other factors such as distribution, patient pH, intravascular volume and oxygenation status affect response to ILE. Restoration of intravascular volume and oxygenation should be corrected prior to initiating ILE treatment.
Submitted by: William Pullin, DVM, DACVIM
1. Fernandez, AL, Lee JA, Rahilly L, et al. Use of intravenous lipid emulsion as an antidote in veterinary toxicology. J Vet Emerg Crit Care 2011 Aug;21(4):309-20. doi: 10.1111/j. 1476-4431.2011.00657.x
2. Gwaltney-Brant S, Meadows I. Use of intravenous lipid emulsions for treating certain poisoning cases in small animals. Vet Clie North Am Small Animal Pract. 2012 Mar;42(2): 251-62, vi. doi:10.1016/j.cvsm.2011.12.001
3. Clarke DL, Lee JA, Murphy LA, Reineke EL. Use of intravenous lipid emulsion to treat ivermectin toxicosis in a Border Collie. J Am Vet Med Assoc. 2011 Nov 15;239(10):1328-33. doi: 10.2460/javma.239.10.1328
6. Maton BL, Simonds EE, Lee JA, et al. Use of high-dose insulin therapy and intravenous lipid emulsion to treat severe, refractory diltiazem overdose in a dog. J Vet Emerg Care. 2013 May/June ;23(3):321-7. don 10.1111/vec.12053
7. Herring JM, McMichael MA, Corsi R, Wurlod V. Intravenous lipid emulsion therapy in three cases of canine naproxen overdose. J Vet Emerg Crit Care (San Antonio). 2015 Sep-Oct; 25(5):672-8. doi: 10.1111/vec.12307
11. Peacock R, Hosgood G, Swindells KL, Smart L. Randomized, controlled clinical trial of intravenous lipid emulsion as an adjunctive treatment for permethrin toxicosis in cats. J Vet Emerg Crit Care. 2015 Sep-Oct;25(5):597-605. doi: 10.1111/vec.12322
12. Seitz MA, Burkitt-Creedon JM. Persistent gross lipemia and suspected corneal lipidosis following intravenous lipid therapy in a cat with permethrin toxicosis.J Vet Emerg Crit Care 2016 Nov-Dec;26(6):804-8
13. Cave G, Harvey M, Shaw T, et al. Comparison of intravenous lipid emulsion, bicarbonate, and tailored liposomes in rabbit clomipramine toxicity. Acad Emerg Med. 2013 Oct;20(10): 1076-9. doi 10.111/acem.12224
14. Litz RJ, Roessel T, Heller AR, Stehr SN. Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection. Anesth Analg. 2008;106:1575–1577. doi: 10.1213/ane.0b013e3181683dd7
15. Mizutani K, Oda Y, Sato H. Successful treatment of ropivacaine-induced central nervous system toxicity by use of lipid emulsion: effect on total and unbound plasma fractions. J Anesth. 2011 Jun;25(3):442-5
16. Young AC, Velez LI, Kleinschmidt KC. Intravenous fat emulsion therapy for intentional sustained-release verapamil overdose. Resuscitation. 2009;80:591–593. doi: 10.1016/ j.resuscitation.2009.01.023
17. French D Armenian P, Ryan W, et al. Serum verapamil concentrations before and after Intralipid therapy during treatment of overdose. Clin Toxicol (Phila). 2011 Apr;49(4):340-4. doi 10.3109/15563650.2011.572556
18. Nair F, Paul FK, Protopapas M. Management of near fatal mixed tricyclic antidepressant and selective serotonin reuptake inhibitor overdose with Intralipid 20% emulsion. Aneasth Intensive Care. 2013 Mar;41(2):264-5
19. Han SK, Jeong J, Yeom S, Ryu J, Park S. Use of a lipid emulsion in a patient with refractory hypotension caused by glyphosate-surfactant herbicide. Clin Toxicol (Phila) 2010;48(6):566– 568. doi: 10.3109/15563650.2010.496730
21. (Weinberg GL, VadeBoncouer T, Ramaraju GA, et al. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivicaine-induced asystole in rats. Anesthesiology 1998; 88(4): 1071-1075.)
Treatment of a well-differentiated hepatocellular carcinoma with CyberKnife stereotactic radiation therapy
The patient, an 11-year-old FS Golden Retriever, presented to a referral hospital where she was diagnosed with a low grade hepatocellular carcinoma (HCC). The only clinical sign present was an increase in ALT of 137 (reference range ALP 0-120) and ALP of 427 (reference range 0-140) which was found on routine bloodwork. An ultrasound revealed a 13 x 8 cm isoechoic mass occupying the right medial and portions of the right lateral liver lobes. The mass was mostly solid but with an approximately 5 x 6 cm hypoechoic region which appeared cavitated. Tru-cut biopsies were obtained of the mass and histopathology confirmed low grade HCC. Thoracic radiographs were free of metastatic disease. Due to the location and size of the mass within the liver, surgical resection was not deemed a reasonable treatment option. Other pertinent medical history included complete resection of a low grade mammary carcinoma nine months prior to diagnosis with HCC.
The patient was referred to a second specialty hospital for stereotactic radiation therapy in the form of CyberKnife. This type of radiation therapy is the delivery of a highly conformal dose of radiation therapy to a target with steep dose gradients resulting in a very low dose of radiation being delivered to surrounding normal tissue. This form of therapy relies on highly accurate target localization and precise delivery of radiation. The accuracy associated with this type of RT results in the ability to deliver a higher dose of radiation more rapidly with less normal tissue toxicity.
Prior to treatment with radiation, the patient underwent ultrasound-guided fiducial marker placement in the solid portions of the tumor to allow accurate localization of the tumor during the radiation treatments and a planning CT scan in order to define the tumor and surrounding healthy tissue such as the GI tract, lungs, spinal cord and kidneys. The patient received 3 treatments of CyberKnife stereotactic radiation therapy for a total dose of 30 Gy within a one week time period. Due to motion of the tumor with each phase of respiration, tracking was used in the form of Synchrony cameras which can track the motion of the tumor in “real time” and continuously deliver radiation as the tumor moves. The patient did well for each of her treatments and was discharged from the hospital successfully.
Three months after treatment, the patient had a repeat abdominal ultrasound performed which revealed that the tumor had decreased in size to 5 x 5 cm. Bloodwork at that time revealed an ALT of 242 (reference range 18-121 U/L) with all other values being within normal limits. Another repeat ultrasound was performed in 6 months after treatment which revealed that the tumor had further decreased in size to 3.7 x 4.1 x 4.1 cm. Bloodwork at this point showed that ALT had decreased to 180 (reference range 18-121 U/L). All other values were within normal limits.
In human medicine, stereotactic radiation therapy is becoming more routinely used for non-resectable HCC. Doses of 30-60 Gy are typically used over 3-6 treatments. 1-4 In these cases, other options for treatment include arterial chemoembolization or conformal fractionated external beam radiation therapy. The latter treatment modality has been limited in the past due to the risk of radiation-induced liver disease (RILD). RILD is a sub-acute form of liver injury due to radiation damage to normal, healthy liver tissue surrounding the tumor. It typically occurs 4-8 weeks after completion of RT but has been described in humans as late as 7 months after radiation. Clinical signs of classical RILD include fatigue, abdominal pain, hepatomegaly, ascites and elevation of alkaline phosphatase out of proportion to other liver enzymes. A second form of RILD (non-classical) include jaundice and markedly elevated serum transaminase. 5 In the patient being currently described, the decision to use a radiation dose at the low end of typical human doses was due to the proximity of the mass to the stomach and our attempt to avoid normal tissue toxicity. A moderate elevation in ALT was noted after therapy, which may have correlated with a low grade RILD, however, other abnormal clinical signs associated with typical RILD were not observed.
In veterinary medicine, to the author’s knowledge, there are no studies evaluating the use of stereotactic radiation therapy to treat HCC, however, one study exists which evaluates a more traditional form of radiation therapy in the form of 3D conformal external beam radiation therapy. This modality is capable of delivering equivalent doses of radiation, however, the precision and accuracy of stereotactic radiotherapy is lacking, resulting in a greater possibility of RILD due to the inclusion of larger amounts of normal tissue in the radiation field. However, in the aforementioned study, only 1 of 6 dogs included in the study developed RILD. Individual fraction sizes ranged from 6-10 Gy with the total dose administered being 18-42 Gy over several weeks. Five of 6 dogs had an objective response and median follow-up time was 534 days.6
The tumor tracking capability of CyberKnife Synchrony cameras has been shown in human medicine to significantly reduce the volume of normal liver tissue included in the radiation field, while maintaining high precision in tumor localization, conformity and tumor coverage. This may be especially useful in patients with preexisting liver disease or poor liver function in which they are at a higher risk for developing RILD. 1
This case report demonstrates the successful treatment of a dog with non-resectable low grade HCC with stereotactic radiation therapy. Consideration can be given in the future to dose escalation in which a higher dose of radiation can be given over 3 doses, or more doses can be added to the treatment protocol for a higher cumulative dose.
1. Gated Volumetric-Modulated Arc Therapy vs. Tumor-Tracking CyberKnife Radiotherapy as Stereotactic Body Radiotherapy for Hepatocellular Carcinoma: A Dosimetric Comparison Study Focused on the Impact of Respiratory Motion Managements. Yoon K, Kwak J, Cho B, Park JH, Yoon SM, Lee SW, Kim JH. PLoS One. 2016 Nov 22;11(11):e0166927. doi: 10.1371/journal.pone.0166927https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119818/
2.Stereotactic body radiotherapy for primary hepatic malignancies – Report of a phase I/II institutional study. Weiner AA, Olsen J, Ma D, Dyk P, DeWees T, Myerson RJ, Parikh P. Radiother Oncol. 2016 Oct;121(1):79-85. doi: 10.1016/j.radonc.2016.07.020. http://www.thegreenjournal.com/article/S0167-8140(16)31236-1/abstract
3. Stereotactic Body Radiotherapy for Hepatocellular Carcinoma. McPartlin AJ, Dawson LA. Cancer J. 2016 Jul-Aug;22(4):296-301. doi: 10.1097/PPO.0000000000000201. http://journals.lww.com/journalppo/Abstract/2016/07000/Stereotactic_Body_Radiotherapy_for_Hepatocellula r.10.aspx
4.Stereotactic Body Radiotherapy for Hepatocellular Carcinoma Resulting in a Durable Relapse-Free Survival: A Case Report Monitoring Editor: Alexander Muacevic and John R Adler Samual Francis,1 Ned Williams,1 Christopher J Anker,2 Akram Shaaban,3Robin Kim,4 Dennis Shrieve,1 and Jonathan Tward1Cureus. 2016 Oct; 8(10): e841. Published online 2016 Oct 24. doi: 10.7759/cureus.841 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120964/
5. Radiation induced liver disease: A clinical update R. Bensona, R. Madana, , , R. Kilambib, S. Chandera Journal of the Egytial National Cancer Institute. 2016 March 28 (1) 7-11 http://www.sciencedirect.com/science/article/pii/S1110036215000849
6.Three-dimensional conformal radiation therapy for inoperable massive hepatocellular carcinoma in six dogs. J Small Anim Pract. July 2015;56(7):441-5. T Mori 1, Y Ito 1, M Kawabe 1, R Iwasaki 1, H Sakai 2, M Murakami 1, K Maruo 1http://onlinelibrary.wiley.com/doi/10.1111/jsap.12352/abstract
SRMA, also known as corticosteroid responsive (aseptic) meningitis is an auto-immune disease that targets the leptomeninges and associated vessels. The exact cause is unknown. Studies have suggested a Th2-mediated response with elevated Immunoglobulin A (IgA) levels in the CSF and serum. Elevated IL-8 levels have been noted in the CSF which is associated with invasion of neutrophils into the leptomeninges.
SRMA is mostly seen in medium to large breed dogs with the Boxer, Bernese Mountain Dog, Beagle, Golden Retrievers, German Shorthaired Pointers and Nova Scotia Duck Tolling Retriever possibly being predisposed. In the Beagle, SRMA was been previously labeled as ‘Beagle Pain Syndrome’. Although these breeds seem to be overrepresented with SRMA, it can affect almost any breed of dog. SMRA typically occurs in dogs less than 2 years of age.
Classically, dogs with SRMA present with fever and severe spinal pain. A majority of patients will have neck pain. Dogs will often experience severe allodynia (pain from a non-painful stimulus) and/or severe anticipation of pain. When walking, dogs will typically have a short, choppy gait. Frequently, no specific neurologic deficits will be noted (i.e. proprioceptive / reflex deficits). Extreme lethargy and decreased appetite may also be noted.
The diagnosis of SRMA is made by a combination of imaging studies and a cerebral spinal fluid (CSF) analysis. MRI of the most painful region is often recommended to rule out other causes of spinal pain such as a herniated disc, vertebral malformations, and other causes of myelitis (i.e. infectious). MRI is a non-invasive test, but does require general anesthesia to keep the dog still and comfortable during the procedure. If no structural cause for the spinal pain is found the next step is to perform a CSF analysis. The total nucleated cell count (TNCC), protein level and cytology of the spinal fluid will be evaluated. Classically you will see a marked neutrophilic pleocytosis and elevated protein levels.
It is important to note that a neutrophilic pleocytosis not 100% specific for SMRA and common infectious diseases should be ruled out with serum or CSF titers. The infectious disease testing submitted should be determined based on geographical location and specific exposure risks. Frequently tested organisms include Rickettsial diseases, Toxoplasma, Neospora, Cryptococcus, and Distemper virus. Approximately 46% of dogs with SRMA will have a concurrent immune-mediated polyarthritis. The clinical signs (i.e. short and choppy gait) can look very similar therefore the clinician needs to pay special attention to palpation of the joints in dogs with suspected SRMA. Frequently if polyarthritis is suspected, arthrocentesis can be performed after the MRI while the dog is still under anesthesia.
To help aid in the diagnosis of SRMA a C-Reactive Protein (CRP) can be measured. CRP is an acute-phase protein that is produced by the liver in response to inflammation in the body. A dog with SRMA will frequently have a high CRP level. This test is also useful to monitor how a patient is responding to treatment and to identify if they are relapsing.
Corticosteroids are the cornerstone of treatment of SRMA. Typically prednisone is started with a high initial dose (2-4 mg/kg/day) and then tapered slowly over several months. Common side effects of corticosteroids may include increased eating and drinking, behavior changes, gastrointestinal upset, and weight gain. The vast majority of dogs with SRMA will become clinically normal very rapidly; often in as little as 1 or 2 days. Occasionally, dogs with more advanced disease will require additional immuno-modulating medications. Cyclosporine, azathioprine, and mycophenolate are examples of other medications that have been used in conjunction with corticosteroids to help control the disease.
Treatment typically lasts for at least 6 months depending on the patient’s response. Because clinical remission is often rapid, tapering the prednisone too quickly is a common mistake that can trigger a relapse. Many dogs can be weaned off corticosteroids completely if done slowly (~6 months). Ideally a normal CRP should be obtained before attempting to taper medications. Ultimately a repeat CSF analysis may be needed to confirm a relapse. Should a relapse occur the initial corticosteroid dose should be restarted and then taper more slowly than the first attempt. Some dogs may require a low dose of corticosteroids life-long.
SRMA typically has an excellent prognosis. Usually after 24-48 hours of starting corticosteroids the dog is improving if not yet normal. The lack of a rapid positive response to the steroids should indicate to the clinician that SRMA may not be the cause of the clinical signs or the patient has a more severe variation of SMRA.
- Bathen-Noethen A, Carlson R, Menzel D, Mischke R, Tipold A. Concentrations of acute-phase proteins in dogs with steroid responsive meningitis-arteritis. J Vet Intern Med [Internet]. 2008;22(5):1149–56. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2008.0164.x/full
- Dewey CW, da Costa RC. Practical Guide to Canine and Feline Neurology. 3rd ed. 2016.
- Lowrie M, Penderis J, Eckersall PD, McLaughlin M, Mellor D, Anderson TJ. The role of acute phase proteins in diagnosis and management of steroid-responsive meningitis arteritis in dogs. Vet J [Internet]. 2009 Oct;182(1):125–30. http://www.sciencedirect.com/science/article/pii/S1090023308001615
- Lowrie M, Penderis J, McLaughlin M, Eckersall PD, Anderson TJ. Steroid responsive meningitis-arteritis: a prospective study of potential disease markers, prednisolone treatment, and long-term outcome in 20 dogs (2006-2008). J Vet Intern Med [Internet]. 2009;23(4):862–70. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2009.0337.x/full
- Tipold A, Schatzberg SJ. An update on steroid responsive meningitis-arteritis. J Small Anim Pract [Internet]. 2010 Mar [cited 2013 Dec 11];51(3):150–4. http://onlinelibrary.wiley.com/doi/10.1111/j.1748-5827.2009.00848.x/full
- Webb A., Taylor SM, Muir GD. Steroid-responsive meningitis-arteritis in dogs with noninfectious, nonerosive, idiopathic, immune-mediated polyarthritis. J Vet Intern Med. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2002.tb02368.x/abstract
The ethics of veterinary practice, particularly oncology, is an interesting topic for numerous reasons and one that should be discussed more frequently and fervently. These ethical dilemmas are perhaps more frequent and challenging for surgical, medical, and radiation oncologists because of the nature of what we do on a daily basis but the relative lack of evidence to support what we do. I am relatively frequently presenting owners with surgical options which have either not been performed before or have been reported in non-peer reviewed list servs and forums; and medical and radiation oncologists will often recommend treatment protocols for diseases for which there are no published studies or there are published studies which show no survival benefit for these treatments. Moreover, we often neglect to consider the potential deleterious effects of these treatments and the impact that these can have on quality of life.
Owners are advocates for their pets and informed consent is necessary prior to starting any treatment. Informed consent is the process of obtaining permission from the patient or, for veterinarians, their owner(s) so that they have an opportunity to decide about their health care. In the medical profession, this definition originates from the legal and ethical rights of the patient and from the ethical duty of the physician to involve the patient in health care decisions.1 Informed consent, at least in theory, has transitioned from a paternalistic approach (whereby the doctor was the only one to make treatment decisions) to a more collaborative approach (whereby the doctor and patient discuss the pros and cons of the various treatment options and the patient decides the treatment option they prefer, with or without guidance from the doctor).1 Unlike our human counterparts, veterinarians are not obligated by legal precedence and our only obligation to our patients and their owners for informed consent is moral rather than legal.2
In “Owner Consent in Veterinary Medicine”, the American Veterinary Medical Association (AVMA) states that the “information received by them (the owner) has been understood, and that they are consenting to the recommended treatments or procedures”.2 This definition reflects the often used paternalistic approach used by many veterinarians whereby owners, despite being informed of the recommended treatment and its associated risks and costs, are not involved in the decision-making process other than to say “yes” or “no” to the recommended treatment. In contrast, the Royal College of Veterinary Surgeons (RCVS) in the United Kingdom (UK) states informed consent “can only be given by a client who has had the opportunity to consider a range of reasonable treatment options, with associated fees, and had the significance and main risks explained to them.”3 Similarly, the Code of Good Veterinary Practice of the Federation of Veterinarians of Europe states that the veterinarian must provide information of the “risks, the costs and benefits of the different and alternative diagnostic and therapeutic routes.”1 The essential difference between the definitions of informed consent between the AVMA and RCVS/Europe is that owners in the UK and Europe are collaborating with their veterinarian in making an informed decision (based on a discussion of the benefits, risks, and costs of a number of procedures and/or treatments) regarding their pet rather than the paternalistic approach favored by the AVMA.
How many of us collaborate with our clients and how many of us adopt the paternalistic approach? How many of us truly involve owners in the decision-making process for their pets by discussing a number of different treatment options, if available, and explaining the risks and benefits of each option and the evidence to support these options? More importantly, how many of us do this impartially and without inserting our own personal biases (unless requested)? Surgical oncologists are perhaps more fortunate than medical and radiation oncologists as we often have more published literature to be able to inform owners on the benefits, risks, and outcomes of surgical procedures. However, we are also bound, at least morally, to inform owners when we do not have studies to support the efficacy of proposed treatment options (for example, surgical re-excisions for narrowly excised tumors, chemotherapy for high-grade soft tissue sarcomas and non-metastatic apocrine gland anal sac adenocarcinomas, and radiation therapy for incompletely excised soft tissue sarcomas) and to discuss the reasons why these treatments may not have provided a beneficial effect on outcome (e.g., retrospective study, low case numbers, heterogenous groups, etc).
As an avid proponent of evidence-based medicine and collaborative informed consent, my two challenges to us all are:
1. If you are not already, do not use the paternalistic informed consent as defined by the AVMA but rather the collaborative informed consent as defined by the RCVS and the Federation of Veterinarians of Europe.
2. When we do not have published evidence for procedures/treatments and when we ignore published evidence in favor of our own opinions because of criticisms of the design and/or interpretation of these studies or disbelief of the results, then this should inspire us to search for this evidence for the benefit of our animals, owners, and profession.
As oncologists, we are a collaborative group of like-minded specialists and clinicians and, as the Veterinary Society of Surgical Oncology has shown since its inception, it is possible to work together to develop large, multi-institutional studies to fill these gaps in our knowledge base and practice evidence-based rather than opinion-based medicine.
Passantino A, Quartarone V, Russo M. Informed consent in veterinary medicine: legal and medical perspectives in Italy. Open Journal of Animal Sciences 1:128-134, 201