pet dept. american blvd. w ... · – drug class: bisphosphonate – blocks dissolution of calcium...
TRANSCRIPT
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Pet Poison Helpline ©20183600 Amer i can B l vd . W. , #725 B loom in g ton , MN 55431www.pe tpo i sonhe lp l i n e . com
Rodenticide Revolution:
d‐CON says, "Good‐bye anticoagulants, hello Vitamin D."
Ahna Brutlag, DVM, MS, DABT, DABVTDirector, Veterinary Services & Sr. Veterinary ToxicologistPet Poison [email protected]&Adjunct Assistant ProfessorDept. Veterinary Biomedical SciencesCollege of Vet. Med., University of Minnesota
August 23, 2018
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Speaker IntroductionAhna G. Brutlag, DVM,
MS, DABT, DABVT
Associate Director of Veterinary Services
&
Senior Veterinary Toxicologist
Pet Poison Helpline
Minneapolis, Minnesota
&Adjunct Assistant Professor
College of Veterinary Medicine University of Minnesota
Today’s topics
• Review of rodenticide changes in US
• Brief review of anticoagulants & bromethalin
• In‐depth review of cholecalciferol toxicosis
– Toxic dose
– Clinical signs
– Diagnosis
– Treatment
Rodenticide History Lesson
• Before 2008: 2nd generation anticoagulant most common in homes
• 2008 Risk Mitigation Decision
– In effect by June 2011
– Major change in EPA regulation
– ‘Consumer’ vs ‘Ag/Professional’ products
– No 2nd generation anticoagulants in homes*
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1st gen vs 2nd gen anticoagulants
• 1st generation
2011 EPA Regulatory Changes
Consumer Product
1 pound max
Must include bait station
OK to sell in all retail stores &
farm stores
Limited to:
1st generation anticoagulants
Bromethalin (neurotoxicant)
Cholecalciferol (Vit D3)
Zinc phosphide
No 2nd generation anticoagulants!
Only block or soft baits
Prohibit: meal, pellets, liquids
Ag & Professional Product
4 pound minimum
No bait station requirement
No selling in grocery stores, big box, etc.
Sold only agricultural, farm, tractor stores
Everything allowed in “consumer size” and 2nd generation anticoagulants.
Pellets, “meal”, pastes, blocks, etc, allowed
PackageSize
Place of Sale
Active Ingredients
AllowedFormulation
0%
10%
20%
30%
40%
50%
60%
70%
80%
2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Percentage of PPH Rodenticide Cases by Active Ingredient (2009‐2018 July 31)
2nd gen AR 1st gen AR Bromethalin Cholecalciferol
1st Generation Anticoagulants• Chlorphacinone• Diphacinone• Warfarin
2nd Generation Anticoagulants• Brodifacoum• Bromadiolone• Difethialone
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0%
10%
20%
30%
40%
50%
60%
70%
80%
2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Percentage of PPH Rodenticide Cases by Active Ingredient (2009‐2018 July 31)
2nd gen AR 1st gen AR Bromethalin Cholecalciferol
1st Generation Anticoagulants• Chlorphacinone• Diphacinone• Warfarin
2nd Generation Anticoagulants• Brodifacoum• Bromadiolone• Difethialone
New EPA regulations go into effect
QUICK REVIEW
Anticoagulants & bromethalin
Anticoagulant Review
• 1st and 2nd generation
• Inhibit production of Vitamin K dependent clotting factors (2, 7, 9, 10)
• Signs 3-5 days after ingestion• Tests: PT preferred• Treatment: Oral vitamin K1
For full review watch archived PPH webinar Rodenticides: It’s more than just Vitamin K!
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Anticoagulant Clinical Signs• Dyspnea (57%)
• Lethargy (48%)
• Coughing/hemoptysis (30%)
• Pallor (26%)
• Epistaxis (17%)
• Vomiting (17%)
• Melena (17%)
• Hematochezia (13%)
• Lameness (13%)
• Hematoma (15.9%)
• Ecchymoses (13%)
• Hematuria (2.9%)
• Gingival bleeding (9%)
• Collapse (2.9%)
• Anorexia (1.4%)
• Abdominal distension (1.4%)
• Abdominal pain (1.4%)
• Shaking (1.4%)
• Cats: Otic hemorrhage
Sheafor SE, Couto CG. Anticoagulant Rodenticide toxicity in 21 dogs. J Am Anim Hosp Assoc. 1999;30:38‐46
Bohn B, Weingart, Giger U. Hemorrhage in seven cats with suspected anticoagulant rodenticide intoxication. J Fel Med Surg 2003;5:295‐304
Radiographs from dog with clinical anticoagulant rodenticide poisoning
http://www.boulesdefourrure.fr/
Bromethalin Review
• Tomcat
• Victor Fast‐Kill
• Fastrac Blox
• Talpirid
• Other mole and gopher bait!
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Interspecies Differences
• Cats 10 x more sensitive than dogs
• Cat LD50: 0.54 mg/kg
– Lowest toxic dose reported 0.24mg/kg
• Dog LD50: 3.7 mg/kg
– Lowest toxic dose reported 1‐1.5mg/kg
Bromethalin: CNS ToxicityCerebral and spinal cord edema intracranial pressure
neurological disturbances paralysis or convulsions DEATH
Diffuse spongiosis of cerebral cortical white matter from a dog given bromethalin (6.25 mg/kg) 40 hours earlier. From Dorman et al., J Vet Diagn Invest., 2:123-128, 1990.
Toxic Syndromes in Cats and Dogs
Paralysis(any toxic dose)
Paralysis(toxic dose < LD50)
Convulsions(toxic dose > LD50)
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THE MAIN ACTCholecalciferol
Cholecalciferol
• Also called vitamin D3 & “sunshine vitamin”
– People synthesize D3 from sun exposure
– Cats & dogs __(can or cannot?)_____
• Other Vit D poisoning sources
– Human supplements
– Human topical psoriasis medications (calcipotriol/calcipotriene)
– Plants (mostly grazing animals)
• Considered a hormone
Audience poll!
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 (TO JULY 31)
PERCENTAGE OF PPH RODENTICIDE WITH D3 SUPPLEMENT CASES
(2009‐2018)
Anticoagulants Bromethalin Cholecalciferol Vit D3 Supplements
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d‐CON soft baits
• Each bait weighs ~14 grams– 0.075% cholecalciferol
– ~11 mg D3 (+/‐ 1mg) per bait
• Perforated thin plastic film
• Extremely palatable to rodents
• 99% human food– Contains wheat flour and
vegetable oils
– No soy, corn, beef, or chicken
• Tip: If d‐CON brand & soft bait, guaranteed to be D3!
Other D3 baits in US market
• d‐CON is only D3 consumer bait (as of Aug 2018)
• Remainder are ag/professional use
Other soft baits in USA
• Resolv (bromadiolone)
• First Strike (difethialone)
• Take Down (bromethalin)
• Brigand (bromadiolone)
• Any with D3??
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Cholecalciferol poisoning
• Promotes calcium retention– ↑ Ca and phos absorp on from the GIT– ↑ Ca reabsorp on from the distal tubules– ↑ Ca mobiliza on from the bones
• Toxicosis results in – Hypercalcemia (total serum calcium and iCa)– Hyperphosphatemia– Metastatic tissue mineralization
• Acute kidney injury
• Enterohepatic recirculation occurs
Timeline of D3 Poisoning12‐36 hours
• GI signs initially (anorexia, v/d, +/‐melena)• Weakness, lethargy• PU/PD
12‐72 hours• ↑ Ca, ↑ P
• Total serum Ca > 12.5 mg/dl (> 3.12 mmol/L)• Ionized Ca > 5.4 mg/dl (> 1.33 mmol/L)
– Normal iCa 4.5‐5.4 mg/dl (1.13 – 1.33 mmol/L)
• +/‐ K abnormalities 3‐7 days• Metastatic mineralization
– GIT, vasculature, kidneys – Pulmonary mineralization common in cats
• ↑ BUN and crea nine • Hyposthenuria
Calcium X Phosphorus > 60 risk for soft tissuemineralization
PET POISON HELPLINE
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D3 toxic doses• Dose/signs—dogs and cats
– > 0.1 mg/kg
• Anorexia, PU/PD, lethargy, weakness
– > 0.5 mg/kg
• ↑ Ca, ↑ P, ssue mineraliza on, renal failure
– d‐CON bait example: • 0.5 mg/kg = _____ grams bait for 10 lb (4.5kg) cat or dog
• 0.5 mg/kg = _____ grams bait for 35 lb (16 kg) dog
• 0.5 mg/kg = _____ grams bait for 65 lb (29.5 kg) dog
• Large individual sensitivity!
– Canine oral LD50 of 13‐88 mg/kg
• Fat soluble vitamin, concentrates in milk; nursing kittens and puppies are at risk for toxicosis
D3 supplements40,000 IU of D3 = 1 mg
14.3 gram bait
~3
~10.5
~20.5
Bait weighs ~14 grams0.075% cholecalciferol~11 mg D3/bait
PPH recommended management site for D3 rodenticides and supplements
Cholecalciferol Absorption
• Requires presence of fat & bile salts to be absorbed
• Small intestine
– Enters circulation via chylomicrons
• Transferred to Vit D binding protein
– Requires this protein carrier for solubility in plasma
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Half‐life
• Plasma T1/2 of active D3 is short
– 6‐8 hours (human)
– 19‐25 hours (animals)
• Whole body T1/2 is approximately 2 months.
– Stored in adipose tissue
– The vitamin D3 that is deposited in the tissues is VERY slowly metabolized.
D3 Diagnostic Testing
• Monitoring
– Ca or iCa and P at presentation then q 24 hours
• Which one should you use?
• Can you use total Ca to predict iCa?
– Values to watch for
• ↑ Ca, ↑ P– Total serum Ca > 12.5 mg/dl (> 3.12 mmol/L)
– Ionized Ca > 5.4 mg/dl (> 1.33 mmol/L)
» Normal iCa 4.5‐5.4 mg/dl (1.13 – 1.33 mmol/L)
• +/‐ K abnormalities
Audience poll!
Good read on iCa collection: http://www.eclinpath.com/chemistry/minerals/ionized‐calcium/
D3 Diagnostic Testing
• Monitoring con’t…
– BUN/creatinine at presentation then q 24 hours
– UA & USG
• Ca crystalluria and hypsothenuria
– PCV/TS and body weight with all other labs
• Pro tip: Hydration status is key to lab interpretation!
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D3 confirmatory testing?
• Confirmatory testing not common in vet med
• Potential tests– 25(OH)D3 (calcidiol or calcifediol, inactive metabolite)
• primary circulating metabolite created in liver
• may be 15‐20 x normal in poisoning in 24 hours
“Based on a variety of studies in several animal species, it appears that the plasma 25(OH)D concentrations associated with toxicity are always in excess of 375 nmol/L.” Jones, 2008
– 1,25(OH)2D3 (calcitriol, active metabolite)• Not often considerably elevated in poisoning
– Not necessarily consistent with or predictive of hyperCa/P
– Not necessarily prognostic in tox cases
– Protect sample from light
Audience poll!
Treatment Goals
• Reduce GI absorption via decontamination
– Emesis and multi‐dose charcoal
• Keep the serum Ca <12.5 mg/dL or iCa <5.4mg/dL (<1.33 mmol/L)
– Rely on iCa more than total Ca
Detailed information on decontamination in PPH Archived Webinars:Decontamination of the Poisoned Patient: What, Why, When and How (April, 2017)
Treatment• Aggressiveness based on dose, labs, signs• Fluids, fluids!
– IV NaCl, 0.9%, Norm‐R, Plyte @ 1.5‐3 x maintenance
• Bisphosphonates (eg pamidronate)• Increase calciuresis
– Furosemide after patient is well hydrated• 0.66 mg/kg IV bolus followed by 0.66 mg/kg/hr CRI• 1‐2 mg/kg PO BID and wean over 1‐2 weeks
– Prednisone (dogs)/prednisolone (cats) or…• 1 mg/kg q 12 hours
– Dexamethasone• 0.2 mg/kg IV q12hrs
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Goal: Prevent Ca release from bone
• Pamidronate Preferred method
– Drug class: Bisphosphonate
– Blocks dissolution of calcium hydroxyapatite
– Inhibits osteoclastic bone resorption (i.e. inhibits release of Ca from bone)
– 1.3‐2 mg/kg IV diluted in 150‐250 mL saline over 2 hours
– Serum calcium should decrease in 2‐4 days
– Repeat in 5‐7 days if hypercalcemia not responsive or rebounds
• Calcitonin– 4‐6 IU/kg SQ q 2‐3 h until serum calcium is below 12.4 mg/dl. Increase
dose to 10‐20 IU/kg if no effect.
– Rarely used, hard to find, rapid resistance.
Additional treatment• GI support
– Antiemetics– GI protectants– Low Ca diet (eg: k/d, s/d, u/d)
• Phosphate binders• Cholesytramine
– Makes Vit D‐bound bile acids insoluble and unable to be re‐absorbed. Shown to reduce D3 absorption in people but no helpful data in animals regarding D3 poisoning.
– Dose: 0.3‐1g/kg q 8 hours x 4 days, base dose on amount ingested. – Conclusion: Unknown if truly helpful but unlikely to harm.
• Poisoning can take weeks/months to resolve– Consistent lab monitoring essential
Diagnostic Quandaries & Tips
• Quandary: Calcium Phosphorus Solubility Index (CPSI)
– CPSI= Calcium (total) x Phosphorus
– Adult dogs and cats: CPSI <60
– Growing puppies: CPSI <80
– What does this really mean? Good evidence? Realistic?
• Quandary: Age
• Tip: Use your iCa!
• Tip: Check PCV/TS!
3‐8 wks 8‐16 wks 16‐1 yr >1 yr
Total Calcium mg/dL (normal =
7.6 ‐ 13.43 3.13 – 13.55 7.82 – 13.75 9.82 – 11.82
Phosphorous mg/dL 3.0 ‐ 10.72 2.91 – 10.31 2.51 – 9.01 2.11 – 10.65
Modified from Harper, et al. Age‐related variations in hematologic and plasma biochemical test results in Beagles and Labrador Retrievers. JAVMA, 2003
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Relay toxicity?• Cats
– Very rare with acute/sub‐chronic exposure• 12 feral cats fed D3 poisoned possums as their sole food for 5 days showed no changes in blood work or body weight (followed every week x 7 weeks). Eason, 2000
• Dogs– Susceptible but unlikely
• 22 stray dogs fed whole carcasses of possums that were fed 0.8% cholecalciferol bait and either euthanized at 48 hours or allowed to die naturally for 1, 2 or 5 days. These dogs were monitored and euthanized at 14 or 28 days post ingestion. All had signs of toxicity with the group being fed the euthanized possums experiencing the most signs. Eason, 2000
Wrap up
• d‐CON switching all consumer baits to Vit D3 soft baits
• Fewer anticoagulant rodenticides in homes
• Look out for bromethalin rodenticides
• Cholecalciferol causes ↑ Ca, ↑ P, kidney failure– iCa preferred over total Ca
– Use PCV/TS and patient weight for guidance
– Bisphosphonates to reduce serum Ca
– Beware normal Ca & P in young animals—don’t over treat
• Testing and treatment may be lengthy
Sign up for…Quarterly Newsletters Video Series
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Tox Goodies!Free to order: [email protected]
Blackwell’s Five‐Minute Veterinary Consult Clinical Companion:
Small Animal Toxicology 2nd Edition
Drs. Lynn Hovda, Ahna Brutlag, Robert Poppenga, Katherine Peterson
www.wiley.com/go/vet
Paperback | May 2016 | 960 pages | 978‐1‐119‐03654‐8 | $109.99 ∙ CAN $120.99
• Provides concise, bulleted information focused on the most important facts needed when treating a poisoned cat or dog
• Carefully organized for ease of use in an emergency, with important toxicants arranged alphabetically within categories
• Details clinically relevant information on the most common toxicants encountered by small animals
• Presents a wealth of color photographs to aid in plant identification
• Includes 14 new topics to this edition covering cyclosporine A, sleep aids, tacrolimus, bath salts, synthetic marijuana, poisonous lizards, imidacloprid, spring bulbs, and sodium monofluoroacetate
PPH is hiring!
• Veterinary technician openings
– Work from the comfort of your home!
• Hire from 20 states
– FT evening/weekend hours now available!
– We offer competitive pay and benefits!
• Always accepting resumes for future hiring needs
• Questions? Need more info? Visit our careers page at petpoisonhelpline.com/veterinarians/job‐opportunities or email [email protected].
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2018 CE Schedule
Free, RACE‐Approved Webinars
Thank you for attending!
CE credit FAQs1. When will I get my CE certificate? We’ll email it to you by the end of the day tomorrow.
2. I attended the webinar but wasn’t the person who logged in. Can I still get interactive CE credit? Yes. Send your name and email address to [email protected] by 1pm central time on Aug 24, 2018 (strict deadline).
3. Can I watch the recorded webinar online for CE credit? Yes. You can receive non-interactive CE credit. Go to the “For Vets” page on our website, www.petpoisonhelpline.comfor more info.
Comments? Questions? Email us! [email protected]
Acknowledgments
• Thanks for your help and previous work!
– Dr. Amanda Poldoski @ Pet Poison Helpline
– Dr. Katie Peterson @ Pet Poison Helpline
– Dr. Cat Angle @ Hill’s Pet Food
– Dr. Dave Brown @ Univ of MN, Coll of Vet Med
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For reference: Vitamin D and select metabolites.
Metabolites most pertinent to D3 tox highlighted.Table 1. Important Vitamin D Forms
Name Alternate Name Formula Description
Ergocalciferol Vitamin D2 NA Plant‐based form
Cholecalciferol Vitamin D3 NA Animal‐based form; form produced in human skin
Ercalcidiol 25‐hydroxyvitamin D2 25(OH)D2 Main circulating form of vitamin D2
Calcidiol or calcifediol 25‐hydroxyvitamin D3 25(OH)D3 Main circulating form of vitamin D3 (inactive)
Ercalcitriol 1,25‐dihydroxyvitamin D2 1,25(OH)2D2 Active form of vitamin D2; has a short half‐life in the blood
Calcitriol 1,25‐dihydroxyvitamin D3 1,25(OH)2D3 Active form of vitamin D3; has a short half‐life in the blood
3‐epimer 3‐epi‐25‐hydroxyvitamin D 3‐epi‐25(OH)D Low‐activity form; significant levels present in infants
Answers to poll questions are highlighted
• Cats and dogs _(can or cannot)_ make sufficient vitamin D3 from the sun?– Can– Cannot
• Is it better to measure total Ca or iCa in cases of D3 poisoning?– Total– Ionized
• Can you use total Ca to predict iCa?– Yes– No
• In cholecalciferol poisoning, intact PTH is:– Elevated– Decreased
Selected & recommended references
• Adams C. Cholecalciferol. In: Blackwell’s Five‐Minute Veterinary Consult ‐ Small Animal Toxicology. Osweiler, Hovda, Brutlag, Lee (Eds). Wiley‐Blackwell, Ames, IA, 2010, pp875‐890.
• Cline J. Calcium and vitamin d metabolism, deficiency, and excess. Topics in Compan An Med 2012;27:159
• Eason CT, Wickstrom M, Henderson R, et al. Non‐target and secondary poisoning risks associated with cholecalciferol. New Zealand Plant Protection 53:299‐304, 2000
• Finch NC. Hypercalcemia in cats. J Fel Med and Surgery (2016) 18, 387‐399
• Harper EG, et al. Age‐related variations in hematologic and plasma biochemical test results in Beagles and Labrador Retrievers. J Am Vet Med Assoc 2003;223:1436–1442
• Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008;88(suppl)l:582S
• Marshall EF. Cholecalciferol: a unique toxicant for rodent control. Proceedings of the eleventh vertebrate pest conference. Lincoln, NE, 95‐98, 1984.
• Morita T, Awakura T, Shimada A, et al: Vitamin D Toxicosis in Cats: Natural Outbreak and Experimental Study. J Vet Med Sci 57(5): 831‐837, 1995.
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Selected & recommended references, con’t
• O’Neill WC. The fallacy of the calcium‐phosphorus product. Kidney International (2007) 72, 792–796
• Parker VJ et al. Vitamin D metabolism in canine and feline medicine. J Am Vet Med Assoc 2017:250(11):1259
• Rumbeiha WK, Kruger JM, Fitzgerald SF, et al: Use of pamidronate disodium to reverse vitamin D3 induced toxicosis in dogs. AJVR 60(9):1092‐1097, 1999.
• Rumbeiha WK. Cholecalciferol. In Peterson/Talcott Small Animal Toxicology 2013
• Schneck PA and Chew DJ. Calcium: Total or ionized? Vet Clin Small Anim 38 (2008) 497–502
• Selting KA, et al. Serum 25‐hydroxyvitamin D concentrations in dogs ‐ correlation with health and cancer risk. Vet Comp Oncol. 2016 Sep;14(3):295‐305
• Sharp CR, et al. The effect of diet on serum 25‐hydroxyvitamin D concentrations in dogs. BMC Res Notes. 2015 Sep 15;8:442
• Sih TR, et al. Chronic ingestion of high concentrations of cholecalciferol in cats. Am J Vet Res 2001;62:1500
• Thomas JB, Hood JC, Gaschk F. Cholecalciferol rodenticide toxicity in a domestic cat. Aus Vet J 67(7):274‐5, 1990.
• Wehner A, Katzenberger J, Groth A, Dorsch R, Koelle P, Hartmann K, Weber K. Vitamin D intoxication caused by ingestion of commercial cat food in three kittens. Journal of Feline medicine and Surgery 15(8) 730‐736.