Decontamination Strategies PDF

Decontamination Strategies VM508 Veterinary Toxicology Birgit Puschner, DVM, PhD, Dipl ABVT Veterinary Toxicologist [email protected] Learning Objectives Carry out exposure assessment Explain primary methods for gastrointestinal decontamination Summarize intralipi...

Decontamination Strategies VM508 Veterinary Toxicology Birgit Puschner, DVM, PhD, Dipl ABVT Veterinary Toxicologist [email protected] Learning Objectives Carry out exposure assessment Explain primary methods for gastrointestinal decontamination Summarize intralipid emulsion and its use in intoxications Critique the factors that influence the decisions in decontamination approaches Compare decontamination approaches between species Explain the concepts to increase clearance of systemically absorbed toxicants (not covered here) What is the goal of decontamination? A. Prevent or decrease absorption B. Modify metabolism of the toxicant C. Decrease elimination D. Enhance tissue distribution Decontamination Route Quick tip Ocular Flush with copious amounts of water or physiological saline (> 15 min) Dermal Wash with mild detergent, protect oral exposure (licking); protect yourself Gastrointestinal Emesis, gastric lavage Cathartics, activated charcoal (or other adsorbents) After systemic absorption Forced diuresis Ion trapping Lipid emulsion Factors to consider BEFORE initiating decontamination Inherent toxicity (i.e. LD50, minimum oral lethal dose, etc) Toxicokinetics Time until onset of clinical signs Duration of clinical signs Target tissues Amount ingested Co-exposure to other toxicants Prior intervention (induced vomiting at home, spontaneous emesis) Species, breed and age Underlying disease (e.g. decreased metabolic efficiency) Which of the listed animals can vomit? A. Rats B. Rabbits C. Horses D. Cows E. Guinea pigs Inducing Emesis in Dogs Apomorphine Apomorphine Stimulates dopamine-2 receptors in No FDA approval in the US for emesis in CRTZ dogs 0.03 mg/kg IV – rapid, reliable Extra-label dosing for inducing emesis in 0.03 mg/kg SQ dogs 0.06 mg/kg Intranasal (IN) – reliable, effective Opioid derivative (controlled substance) 0.03 mg/kg Transconjunctival - crush tablet for conjunctival administration Not as effective as IV, SQ, or IN Give naloxone if too sedate; will not reverse vomiting Inducing Emesis in Dogs – Ropinirole (Clevor ™) Mechanism: Dopamine receptor agonist with high selectivity for the D2-like receptors (D2, D3, D4) No dopamine D1 activity No opioid receptor activity Antidote: Metoclopramide (D2 receptor antagonist) Formulation: Ophthalmic solution in single use ampule package contains a chart11 to determine the number of drops needed to obtain a target dose of 3.75mg/m 2 95% efficacy Vomiting typically within 10 minutes (up to 30 min) Advantages: Easy to administer FDA approved for dogs Not a controlled substance like apomorphine https://vetmed.illinois.edu/2022/07/27/pharmacists-corner-clevor-ropinirole-vs-apomorphine-for- emetic-use-in-dogs/  Hydrogen peroxide use in dogs 3%, fresh, bubbly, non-expired Gastric irritant 1-2 ml/kg Inducing Emesis in Cats No hydrogen peroxide or apomorphine! Alpha-2 agonists Dexmedetomidine or xylazine Serious effects: Excessive sedation Cardiovascular collapse Reverse: Antipamezole or yohimbine Hydromorphone Mu-opioid receptor agonist Reverse: naloxone Dexmedetomidine and Xylazine in cats Thawley and Drobitz: JAVMA (2015) Willey et al.: JAVMA (2016) 43 cats in study 47 cats in study Hydrogen peroxide: 0/3 (0% emesis) Hydrogen peroxide: 0/3 (0%) Dose 1.5-2 mL/kg 1.5-2 mL/kg Xylazine: 11/25 (44% emesis) Xylazine: 9/21 (43% emesis) Median time to emesis 10 Dose 0.4-0.6 mg/kg IM minutes Dose 0.4-0.5 mg/kg IM Dexmedetomidine: 13/16 (81% emesis) Dexmedetomidine: 15/26 (58% emesis) Median time to emesis 5 minutes Dose 6-18 mcg/kg IM Median dose 7 mcg/kg IM Median dose 3.5 mcg/kg IV (% cats vomiting) Main side effect for both compounds was sedation  2019 Publication JVECC Hydromorphone and dexmedetomidine in cats Summary: hydromorphone (0.1 mg/kg SQ) is at least as effective as dexmedetomidine in inducing emesis in cats was associated with a lower sedation score and less decrease in HR compared to dexmedetomidine How not to induce emesis in cats Hydrogen peroxide Not very effective Hemorrhagic gastritis Apomorphine Not effective ↓dopamine2 receptors in CRTZ CNS stimulation Courtesy of Patricia A. Talcott, MS, DVM, PhD, DABVT WIMU Regional Program in Veterinary Medicine How Not to Induce Emesis in Any Species Salt: Hypernatremia Syrup of ipecac: Cardiac effects and prolonged vomiting Digital stimulation: Physical injury Liquid dish soap: Ineffective, aspiration risk Forcing water: Aspiration Raw eggs/Tabasco/Mustard: Ineffective Usefulness of emetics depends on time! Emesis advised within 30 min after ingestion Gastric content recovery 49% (range 9-75%) with emesis < 30 minutes after ingestion 17-62% within 1 hour after ingestion But useful up to 6 hours after ingestion for: Grapes, raisins Chocolate Xylitol gum Bezoars Massive ingestions Drugs that decrease gastric emptying Opioids Salicylates Anticholinergics Tricyclic antidepressants  Contraindications to Emesis High risk of aspiration (neurologically depressed, unconscious patient, loss of gag reflex, hypoxia) Already vomited History of seizures Corrosive agent pH 11 Hydrocarbons Oil, gasoline, kerosene Sharp/dangerous objects Non-toxic ingestion Exposure Assessment - Metaldehyde Information given: 2 horses in a shed, both approximately 1000 pounds Got into a container with snail & slug bait Metaldehyde concentration in bait: 2.75% Container volume: 2.5 pounds Calculation: was this a toxic dose? Are the horses in trouble? Question – Select one answer: A. I am confident with this type of calculation B. I can get there with a little bit of review C. I feel pretty lost Exposure Assessment – Metaldehyde What information do we need to obtain first?  Toxicity data Consult literature/toxicologist: Oral LD 50 of metaldehyde in horses: 60 mg/kg What assumptions should we make? One horse ingested all 1000 pounds in kg? 1000 pounds : 2.2 = 454 kg bw 2.5 pounds in kg? 2.5 pounds : 2.2 = 1.13 kg of bait 2.75%: 2.75 g toxicant in 100 g of bait. How much metaldehyde (x) is in 1.13 kg of bait? = x = 31 g (amount of metaldehyde in 1.13 kg of bait) On a mg/kg basis: 31 g/454 kg = 0.06 g/kg = 60 mg/kg Assessment: Exposure is right at the LD50 and must be considered potentially lethal!  Gastric Lavage – more harm than good? When emesis is ineffective or contraindicated Effectiveness: questionable! May require tranquilization/anesthesia Drug recovery 38-29% if within 15 to 20 Airway protection mandatory min Use as large a gastric tube as possible Drug recovery 13-8.6% if delayed until 1 Make sure it is placed appropriately Use tepid tap water or normal saline (5 to 10 hour after ingestion ml/kg) Introduce with minimal pressure  practical clinical success of this Withdraw by aspiration or gravity flow decontamination procedure is Repeat until washings are clear questionable https://www.youtube.com/watch?v=5W5AfyqfNNU Adsorbents Compounds adsorb the toxicant  reduce or prevent systemic absorption if given orally Best known adsorbent: Activated charcoal (AC) Activated charcoal – What is it? Derived from carbonaceous material (wood, coconut, bamboo, peat) Created at high temperatures (600-900°C) and oxidizing agents to form a maze of pores  large functional surface area for its volume Network of fine pores (10 to 20 nm in size) that looks like honeycombs under a microscope Adsorption is due to hydrogen bonding, ion-ion, dipole and van der Waals’ forces Only pharmaceutical grade powdered AC is suitable for clinical use How much AC provides the surface area equivalent to a football field? A. 1 teaspoon B. 1 tablespoon C. 1 ounce D. 1 pound E. 1 kg  AC in Veterinary Use Liquid formulations: suitable for administration by nasogastric or gastric tube. Gel formulations are intended for oral administration. Extruded or beaded activated charcoals are considerably less porous and are not suitable for use for adsorbing xenobiotic. Activated charcoal biscuits, tablets, or capsules have limited adsorbing capacity. AC – is it the Universal Antidote? Does not work well under these Works well under these conditions: conditions: Large molecules (up to 1000 Da) Very small molecules < 100 D: metals and minerals (Pb, As, F, I, Fe, Na) Non-polar molecules cyanide < 2 hours since ingestion ammonia Alert, cooperative patient Alcohols: ethylene glycol, xylitol Intact airway Strongly ionized compounds such as sodium chloride or potassium nitrate Strong acids and bases (think caustics) Petroleum products Activated charcoal - single dose Single dose: 1-5 g/kg of AC (powdered) In water: 1 g AC in 5 ml water If AC + sorbitol: same dose AC Sorbitol at 3 mg/kg; mixed in with AC Do not repeat dose with sorbitol (risk for hypotension and hypovolemic shock) Activated charcoal dose – multiple dose Indication Multiple doses: Large ingestions 0.5 – 1 g/kg of AC without a Sustained release formulations cathartic Enterohepatic recirculation of Every 6-8 hours for 3-4 doses toxicant Important: adequate hydration High concentration of “free” Monitor Na toxicant in circulation (“gut When to stop: significant dialysis” effect) clinical improvement and passage of AC in stools  Contraindications for Activated Charcoal Dehydration Hypernatremia Hypovolemic shock Decreased GI motility/Ileus/obstruction Recent surgery Protracted vomiting Ingestion of a caustic substance or hydrocarbon ↑ aspiration pneumonia Plan to do endoscopy Charcoal? Not so easy with cats! Give 1-2g/kg of charcoal q. 4 hours X 4 doses! UAA Gel (Universal Animal Antidote) Label instructions: give 1-3 ml/kg (2.2 lbs) Active Ingredients: body weight. For cattle or horses, it is Activated Hardwood Charcoal recommended that the animal be 120 mg/ml administered an entire 300 ml tube, with Kaolin 60 mg/ml (clay) appropriate follow up doses at 8 hour intervals. Positive results have also been Dose: ~ 1/3 charcoal reported for managing cases of crypto in calves. Too good to be true? Rec’d: Give 3x recommended dose  Cathartics: Why do we use them? Speed the transit time of toxicants through the GI tract ↓ time for toxicant absorption ↓ time for desorption of toxicant from AC Most common: osmotic cathartics Saline cathartics: sodium sulfate, magnesium sulfate Saccharide cathartic: sorbitol Mechanism: increased fluid volume within the GI tract  stimulates motility  speeds expulsion of GI contents Most useful for: Elimination of ingested solid toxicants Time-release or enteric-coated compounds Sorbitol Administered as a 70% solution Dose: 1 – 2 ml/kg Typically provided with AC in a slurry solution Should only be given once Of note: Contraindications: Based on current data, there are no definite indications for use of cathartics Lack of bowel sounds alone in the management of the Intestinal obstruction or perforation poisoned patient. Ingestion of a corrosive substance Presence of diarrhea Hypotension or electrolyte abnormalities What’s up with Mineral Oil? Have you been involved in a poisoning case where mineral oil was administered? A. Yes B. No What’s up with Mineral Oil? Laxative for horses and cattle Higher risk for aspiration than other cathartics No longer recommended for use in exposures to lipophilic compounds (like OC insecticides) Do not give with AC (coats AC pores) What would be your decontamination approach? Case History Questions 75 heifers on 100 acres (CA) A. I would administer AC Fed hay the evening before: B. I would not administer AC 3 animals found dead in the AM C. I would administer mineral Cows were fine the night before oil Sick cows: lethargic with diarrhea Field necropsy: nothing remarkable, 8 mo pregnant, bloody around eye and rectum (buzzards) This plant was found in huge amounts in hay Life saving fat! Intravenous lipid emulsion (ILE or IVLE) Intravenous fat emulsion (IFE) Uses: 1960s: Component for nutritional therapy PPN TPN Vehicle for drug delivery (i.e., lipid emulsions) 2003: ILE studied to treat systemic intoxication from local anesthetics 2006: ILE to successfully resuscitate human with bupivacaine poisoning Since 2006: ILE used in other lipophilic drug and toxicant intoxications (in humans: β-blockers, calcium-channel blockers, parasiticides, herbicides, and several varieties of psychotropic agents)  Administration of a large amount of fat to treat intoxications with fat-soluble compounds Historical Experimental Data - 2003 Weinberg et al. (2003) with bupivacaine-induced cardiotoxicity in dogs (n=12). Dose bupivacaine 10 mg/kg over 10 seconds Circulatory collapse in mean of 7 min: HR 1 or 2 respond more likely to ILE therapy High volume of distribution (Vd): The greater the Vd, the more the drug distributes into fat and muscle, away from the serum Note: These agents are less likely to be removed via hemodialysis but good candidates for ILE But: some toxicants that are poorly lipophilic (eg baclofen with LogP of - 1.32) have been reported to respond well to ILE Other physiochemical factors, such as electrostatic interactions and ionization, may influence the response of a toxicant to ILE administration. Examples: Verapamil: LogP = 3.8, Vd = 4.5 Bupivacaine: LogP = 3.4, Vd = 0.7 Ethanol: LogP = -0.1, Vd = 0.5 French D, et al. Partition constant and volume of distribution as predictors of clinical efficacy of lipid rescue for toxicological emergencies. Clinical Toxicology (2011), Early Online, 1–9  Toxicants for which to consider ILE Moxidectin: 2009; first case report to successfully Macrocyclic lactones (eg, ivermectin, moxidectin) treat a puppy with moxidectin overdose Marijuana, synthetic cannabinoids Permethrin Since then: > 30 published case reports or series published in cats, dogs, goats, horses, ponies, rabbits, Bromethalin birds, guinea pigs, lion NSAIDs – ibuprofen, naproxen, carprofen Barbiturates Ivermectin: Pieris japonica https://www.youtube.com/watch?v=0wCsJDGKR1I Tremorgenic mycotoxins amlodipine, amphetamines, baclofen, diltiazem, lamotrigine, local anesthetics, loperamide, minoxidil Intravenous lipid emulsion therapy: A. Is given intramuscularly B. Consists of a 50% fat emulsion C. Is given at well research dosages for veterinary species D. Is a last resort treatment due to significant adverse effects E. Is particularly effective in poisonings with fat- soluble agents ILE – Side effects Interference with other treatment modalities (creation of a lipid sink/shuttle may affect other lipophilic therapeutic drugs administered concurrently with ILE) Hyperlipemia Can interfere with common laboratory testing Recurrence of signs following cessation of ILE therapy (reported in humans) – rebound effect Allergic reactions to the product or its components: Fever, nausea, hypotension, and cardiovascular collapse Fat overload syndrome Fat overload syndrome (FOS) can lead to hyperlipidemia, hepatomegaly, fat Example of corneal lipidosis embolism, icterus, & hemolysis. in a dog, unknown etiology. Hemolysis in 1 dog (Fat overload syndrome?). Recovered after transfusion & supportive care. (Gwaltney-Brant & Meadows, 2012) Pancreatitis? Risk in animals currently unclear Reported Adverse Events – Humans and Rats (causality not always proven) People Pancreatitis (Bucklin, 2013) ARDS (Martin, 2014) Fat overload syndrome (FOS) can lead to hyperlipidemia, hepatomegaly, fat embolism, icterus, & hemolysis. Other: Anaphylaxis, fever, vomiting, tachypnea, dyspnea, acute lung injury, phlebitis. Rats: (Hiller et al, 2010) Triglycerides were elevated immediately after infusion but returned to baseline by 48 hrs. ↑ amylase, AST, BUN at all doses. Histologic diagnosis of myocardium, brain, pancreas, and kidneys was normal at all doses. Microscopic abnormalities in lung and liver were observed at 60 and 80 mL/kg; histopathology in the lung and liver was worse at 1 hr than at 4 and 24 hrs. Reported Adverse Effects (generally rare) (causality not proven) Cats http://www.merckvetmanual.com/mvm/ Unilateral facial pruritis 10 h post ILE. Treated with multimedia/v11723589.html chlorpheniramine, resolved in 8 hrs. (Peacock, et al., 2015) Received other drugs in combo with ILE Gross lipemia, transient (several) Gross lipemia >48 hrs (Seitz & Burkitt-Creedon, 2016) Suspected corneal lipidosis (Seitz & Burkitt-Creedon, 2016) 42 hrs after ILE, symmetrical, panstromal white opacity No uveitis, no aqueous flare. Fundic exam precluded. Example of corneal lipidosis in a dog, ILE dose = 31.5 mL/kg over 120 min unknown etiology. Peacock RE, et al. A randomized, controlled clinical trial of intravenous lipid emulsion as an adjunctive treatment for permethrin toxicosis in cats. J Vet Emerg Crit Care 2015; 25(5): 597–605 Seitz & Burkitt-Creedon. Persistent gross lipemia and suspected corneal lipidosis following intravenous lipid therapy in a cat with permethrin toxicosis. (J Vet Emerg Crit Care 2016; 00(0): 1–5)  ILE in Avians – Macaw & Bald Eagle Macaw: observed eating an entire bromethalin rodenticide brick AC and sorbitol, fluids ILE (loading dose of 1.5 mL/kg over 20 minutes, followed by 23 mL/kg per hour IV for 60 minutes; Intralipid 20%) Bald eagle: near landfill, sternal recumbency, declining mentation Blood lead negative ILE (1.5 mL/kg IV loading dose over 5 minutes followed by 15 mL/kg per hour IV over 60 minutes; Intralipid 20%) Serum was positive for barbiturates Schmidt, Lauren K., et al. "Intralipid Emulsion Therapy for the Treatment of Suspected Toxicity in 2 Avian Species." Journal of avian medicine and surgery 36.4 (2023): 394-399. ILE in a Cat – Bupivacaine poisoning Bupivacaine is the most potent and longest-acting amide-linked local anesthetic (duration of action 4–12 h) Bupivacaine has high lipophilicity, high affinity for sodium channels and high protein-binding properties  greatest cardiotoxic potential of all local anesthetics  CNS signs can also be seen Treatment with ILE 20% (Intralipid 20%) as a bolus of 1.5 ml/kg over 5 mins initiated 20 mins after signs of toxicity were first noted. Mentation markedly improved following the ILE 20% bolus ILE 20% bolus was followed by a 0.25 ml/kg/min continuous rate infusion (CRI) delivered over 30 mins. Full recovery Caulfield, Sarah, Erica Tinson, and Rachael Birkbeck. "Successful treatment of local anaesthetic toxicity using intralipid 20% emulsion following intrathoracic bupivacaine overdose in a cat." Journal of Feline Medicine and Surgery Open Reports 8.1 (2022): 20551169221104552. ILE in a dog – Amphetamine Toxicosis 4 year old FS dog ingested Adderall XR™ (12 mg/kg) Oral median lethal dose for amphetamines ranges from 9- 27 mg/kg An initial bolus of 1.5 ml/kg of IVLE was administered over 5 min, followed by a 0.25 ml/kg/min CRI over 1 h. Harris, Stephanie, et al. "Case report: Successful intravenous lipid emulsion therapy for canine amphetamine toxicosis." Frontiers in Veterinary Science 9 (2022): 938021.  Prospective, multi-center, randomized, controlled clinical trial March, 2011-June, 2012 Western Australia (4 states) 1 vet school (Murdoch University) 12 private ERs 34 cats with suspected permethrin poisoning Hypothesis: Clinical signs would improve with ILE vs saline control. Permethrin/ILE Clinical Trial (Peacock, et al. 2015) Study limitations Not blinded No true exposure confirmation No blood permethrin concentrations Cannot determine if lipid “sink/shuttle” occurred Cannot correlate clinical signs to blood concentrations Cannot correlate doses of concomitant drugs to severity/resolution of signs Cannot determine if ILE or any drugs were re-dosed Cannot determine when other agents were given following T=0 Take home message ILE appears well tolerated in this cohort at 15 ml/kg over 60 min It may hasten recovery when used as an adjunctive therapy May be more economical (lipid is cheaper than methocarbamol) Ivermectin – 20 cats Remained asymptomatic 20 cats given 4 mg/kg ivermectin SQ for ear mites (20x overdose) Ivermectin LogP = 5.83 2 h post, all asymptomatic but treated with ILE 1.5 mL/kg bolus (all cats) + 0.25 mL/kg/min CRI x 30 min for 4 Sphynx cats 6 cats (of the n=16 single bolus) developed signs consistent with intoxication 14-48 h after overdose Mydriasis, ataxia, mild-severe weakness, no menace, stupor, tremors, nystagmus, etc. No serum concentrations measured. Ivermectin – 20 cats Authors’ conclusions: Incidence/severity of intoxication may have been higher if ILE were not preemptively given Low BCS associated with increased severity Feline half-life of ivermectin = 2.5 +/-2.2 days Acknowledge that recovery time is as expected given half-life. Maybe no effect on duration of recovery? Call for laboratory analysis re: ILE/ivermectin Studies with NSAID Toxicoses in Dogs Ibuprofen in dogs Naproxen in dogs Carprofen in dogs Study results: Serum toxicant concentrations decreased after ILE administration Data do not support lipid sink theory Poison Control Centers does not currently recommend ILE for most NSAID intoxications Herring JM et al. Intravenous lipid emulsion therapy in three cases of canine naproxen overdose. J Vet Emerg Crit Care 2015; 25(5): 672–678 Bolfer L et al. Treatment of Ibuprofen Toxicosis in a Dog with IV Lipid Emulsion. J Am Anim Hosp Assoc 2014; 50:136–140. What are reasons for inconsistencies in studying clinical efficacy with ILE? Patients receive other treatments ILE dosing regimen differs ILE compounds differ Exposure to toxicants/drugs differs Serum concentrations of toxicants following ILE not measured Review and self-check What ADME processes can be altered with decontamination strategies and how? For which toxicants is AC not recommended? Explain the consideration when giving AC in combination with sorbitol? Compare and contrast the different emetics for different species. Explain the theory of ILE therapy. Conduct an exposure assessment and interpret the result.