Toxicology: the good, the bad, and the totally awesome (Proceedings)

Decontamination

Decontamination involves emptying the GI tract to reduce toxin exposure or increase elimination. This is the most important way to treat a potential toxicity. The 4 methods of decontamination are induction of emesis, gastric lavage, enemas and administration of activated charcoal.

Induction of emesis

Should be performed with recent toxin exposure. However, emesis should NOT be induced if the animal has ingested substances such as cleaning agents (caustics), petroleum products or detergents. It should not be recommended if the animal is comatose, dyspneic, or obtunded. Do not induce emesis if the animal is actively productively vomiting. Induction of vomiting if often of little benefit after 2-4 hours due to stomach emptying, but may be attempted if the animal is stable.

Dogs

• Hydrogen peroxide – 1 tablespoon per 20 pounds orally. This dose can be repeated. Maximum of 3 tablespoons per dose.

• Apomorphine – 0.03mg/kg IV or (preferred) 0.25mg/kg in the subconjunctival sac. Do not use in cats as it will cause excitation.

• Morphine or Hydromorphone at pre-anesthetic dose SQ

Cats

• Xylazine (cats) – 0.44mg/kg IM or SQ, takes about 30 minutes to work with 75% efficacy. Reverse with yohimbine 0.1mg/kg IV.

Gastric lavage

Should be performed in patients that have ingested caustic materials, have an increased risk of aspiration, are seizuring or if emesis cannot be induced by routine methods. Gastric lavage requires general anesthesia and the placement of a well-cuffed endotracheal tube. Gastric lavage should not be performed without placing an ETT due to the high risk of aspiration. Once the patient is properly anesthetized, measure the length of a stomach tube to the last rib. Mark this on your tube. Pass the tube to the pre-measured mark, double check to ensure that the tube is in the stomach, and begin lavage with large volumes of warm water. Two tubes, one for egress and one for ingress, can be used. Continue until the lavage fluid is clear.

Enemas

Are useful to clear toxins from the lower GI tract or with enterohepatic recycling (such as metaldehydes) by speeding GI transit time. Large volumes of warm water should be used. Many activated charcoal products contain sorbitol, a cathartic. Products containing sorbitol should only be given once due to the risk of severe diarrhea and electrolyte disturbances.

Activated charcoal

Acts by binding charged molecules in the GI tract. Mixing activated charcoal with food will render it inactive, as the charcoal will bind charged molecules in the food instead of the toxin. Activated charcoal should be repeated q4-6 hours for toxins with enterohepatic recycling (especially chocolate, marijuana and bromethalin). Do not give repeated doses of sorbitol-containing products. Any oral medications should be started at least 2 hours after activated charcoal administration. Of all of the decontamination methods, activated charcoal administration is likely the MOST important.

Specific toxins

Non-steroidal anti-inflammatory drug toxicities

NSAIDs exert their mechanism of action by reversible inhibition of cyclooxygenase (and lipooxygenase for Tepoxilin). While most of the prescription drugs are COX-2 specific and/or selective, there is variable cross-reactivity between COX-1 and COX-2. Even a COX-2 specific medication has some cross-reactivity between classes. Recent evidence suggests that COX-2 also has some constitutive functions, including maintenance of stomach and colon mucosa and healing of GI ulcers. The viewpoint that COX-1 is all good and COX-2 is all bad appears to be changing as we investigate its function more.

Early treatment includes decontamination of the GI tract, IV fluid diuresis (for large ingestions) and administration of misoprostol (2-5 mcg/kg TID). Misoprostol works by providing an analogue of PGE2, which acts to maintain GI and renal blood flow. Misoprostol is only helpful when the active form of NSAID is present, and tends not to be useful past 3-4 drug half-lives. While I don't always use it, I may use it for only the first 3 days post-NSAID ingestion. After that time, GI ulcerations may be present but misoprostol will be ineffective and may actually worsen vomiting and diarrhea. Fluid diuresis should be continued for 3-4 drug half-lives (~ 48 hours).

If GI ulceration is present, treatment includes anti-emetics, proton pump inhibitors and sucralfate therapy. Renal failure tends to be reversible in mild cases, although long term renal insufficiency can occur depending on the degree of damage.

Acetaminophen (tylenolr) toxicity

Acetaminophen is far more toxic in cats than in dogs. The mode of action is through a cytochrome P450 induced production of an active metabolite (N-acetyl benzoquinomeime) that binds to glutathione, a natural anti-oxidant. Feline hemoglobin is uniquely sensitive to oxidation, resulting in the formation of methemoglobinemia. In dogs, low glutathione levels lead to hepatic necrosis and lower levels of methemoglobin.

Acetaminophen is available in children's (80mg), regular strength (325mg) and extra strength (500mg) doses. The toxic dose in the cat is 50mg/kg, while in the dog it is 150-200mg/kg. Signs of toxicity in the cat are much more common due to less capacity for glucuronidation. Dogs will eliminate the drug 10 times faster than cats.

Typical clinical signs in the cat include anorexia, salivation, dyspnea, hypothermia, depression, weakness and coma. Facial and forelimb edema occur through an unknown mechanism. Mucous membranes, blood and urine are often chocolate colored. Signs will typically occur within 1-4 hours of ingestion.  Clinical signs in the dog include vomiting, abdominal pain and dark urine and mucus membranes.

Diagnosis is based on history, physical exam findings, the presence of methemoglobinemia, prominent Heinz bodies on peripheral smears (cats) and elevated liver enzymes (dogs). Metabolic acidosis may also be present due to inadequate oxygen carrying capacity and tissue hypoxia.

Treatment consists of standard decontamination, supportive care, and therapy directed at reducing oxidative stress. Methemoglobin is unable to carry oxygen, resulting in tissue hypoxia. N-acetylcysteine directly binds with acetaminophen metabolites to enhance elimination and serves as a glutathione precursor. If given IV, dilute to a 5% solution with 5% dextrose. The dose is 140mg/kg IV or PO loading dose, then 70mg/kg q 6 hours for 7 treatments. Blood transfusions may be necessary as damaged red blood cells are removed from circulation. Transfusions will also improve the blood oxygen carrying capacity. Other proposed therapies include administration of ascorbic acid (Vitamin C) 30mg/kg PO or SQ QID, to help to reduce methemoglobinemia; and cimetidine (5-10 mg/kg IV or IM TID) to reduce metabolism of acetaminophen by the cytochrome P-450 system. The benefit of these therapies has not been investigated.

The prognosis is guarded to poor in cats, with rapidly progressive methemoglobin concentrations, methemoglobin concentrations > 50% and progressive rises in liver values being poor prognostic indicators. The prognosis is more favorable in dogs.

Ethylene glycol

Ethylene glycol is contained in many antifreeze preparations. It is rapidly metabolized via alcohol dehydrogenase to glycoaldehyde, glycolic acid, glycoxalic acid and oxalic acid, producing a severe metabolic acidosis and acute renal failure. Oxalic acid may combine with calcium to form calcium oxalate (monohydrate) crystals in the kidneys and other organs. The toxic dose is 4-6ml/kg in the dog and 1.5ml/kg in the cat.

Three stages of intoxication occur. Stage I occurs within 30 minutes to 12 hours of ingestion and consists of neurological signs, including depression, ataxia, knuckling, stupor and coma. Other signs include anorexia, vomiting, polyuria and polydipsia. Stage II occurs 12-24 hours post ingestion and consists of tachypnea and tachycardia, which frequently go unnoticed by the owner. Stage III is the renal phase, occurring at 24-72 hours post ingestion. Signs include severe depression, vomiting, diarrhea, dehydration, azotemia and oliguric or anuric renal failure.

Diagnosis is made by history, physical exam findings, laboratory values and specific testing. Frequent laboratory abnormalities include severe metabolic acidosis, high anion gap, increased serum osmolality, hypocalcemia, and hypo- or hyperphosphatemia. Azotemia typically occurs at 12 hours in the cat and 36-48 hours in the dog. The presence of calcium oxalate crystals in the urine can occur as early as 6 hours post-ingestion, but this finding is not consistently present.

In-house test kits (EGT Test Kit) test for glycol levels greater than 50mg/dl. However, this test will cross-react with a variety of glycols, including the propylene glycol found in certain moist foods, Toxiban, paintballs, and non-toxic antifreezes. These kits are not reliable in cats as the toxic level in cats is much less than that detected by the kit. Quantitative testing for ethylene glycol levels can be performed at most human hospitals, and is much more sensitive and specific. It is relatively inexpensive (< $100 at most hospitals).

Treatment consists of decontamination, supportive care, and directed therapy. Decontamination should be performed immediately if ethylene glycol ingestion is suspected. Once a diagnosis is made, therapy should be instituted promptly. 4-Methylpyrazole (fomepizole or AntizolR) is a competitive inhibitor of alcohol dehydrogenase and is the preferred treatment. For dogs the recommended dose is 20mg/kg IV once, then 15mg/kg at 12 and 24 hours, then 5mg/kg at 36 hours. Fomepizole is not labeled for use in cats, but it has been shown to be effective at much higher doses. The dose for cats is 124mg/kg IV once, then 31.25mg/kg IV at 12, 24 and 36 hours. Fomepizole can be overwhelmed by massive toxin overdoses, such as those that occur with malicious poisoning. If fomepizole is too cost prohibitive, therapy with ethanol can be attempted. Ethanol has multiple problems, including worsening of acidosis, diuresis, and respiratory and CNS depression. Ethylene glycol testing should be performed at the end of therapy. If positive, treatment should be continued.

In addition to directed therapy, supportive care should be administered. IV fluids should be given at 2-3 times maintenance rate. Weight, CVP, and urine output should be monitored carefully. Early and directed treatment typically results in a good outcome for most patients. However, one clinical study found that all patients that were azotemic upon admission did not survive. Therefore, it is very important that clients seek early, aggressive medical attention.

Moldy garbage intoxication

Penitrem A toxicity is a neurotoxin that affects nerves by increasing the resting potential, facilitating transmission across motor end plates and prolonging the duration of depolarization. Clinical signs include panting, restlessness, hypersalivation, incoordination, and fine muscle tremors that start over the face and head and spread over the entire body. Diagnosis is typically made on history and physical exam findings. Induction of emesis, when appropriate, will often cement the diagnosis. Laboratory findings are nonspecific, including leukocytosis or leukopenia late in the disease, elevations in amylase and lipase, or elevations in CK if tremors are present.

Treatment of Penitrem A toxicity includes standard decontamination and supportive care. There are no specific antidotes. While activated charcoal should be administered, along with enemas. Aggressive crystalloid and colloid support should be instituted to treat shock. Broad-spectrum antibiotic therapy should also be instituted. Muscle tremors can be treated with Methocarbamol (Robaxin) 44.4-222mg/kg slow IV to effect. Seizures may require diazepam or barbiturates for control. GI protectants, including H2 blockers and sucralfate are beneficial. If therapy is instituted early in the course of disease, the progress is fair to good.

Chocolate

The mode of action of chocolate is through methylxanthine toxicosis. Both theobromine and caffeine are methylxanthine alkaloids present to varying degrees in chocolate. Typical clinical signs include vomiting and diarrhea, hyperactivity, polyuria and polydipsia, hyperthermia, hyperreflexia, muscle rigidity, tachypnea, tachycardia, seizures and death. The toxic dose of theobromine is 100mg/kg and the toxic dose of caffeine is 140mg/kg.

Diagnosis is typically based on history and physical exam. Many animals are already vomiting or having diarrhea by the time they are presented to the hospital. There is no specific antidote for chocolate ingestion. Standard decontamination, including enemas, and supportive care are recommended. IV fluids, treatment with diazepam or acepromazine for hyperactivity, and ECG and blood pressure monitoring are recommended. Ventricular arrhythmias can be treated with IV lidocaine CRI. Propranolol or metoprolol can be used to control sinus tachycardia. Many dogs will benefit from anti-emetics and GI protectants to neutralize the gastric irritation caused by caffeine toxicosis. The expected clinical course is 12-36 hours. The overall prognosis is good depending on severity of clinical signs. Seizures and arrhythmias are poor prognostic indicators.

Rodenticides

There are three major rodenticides: anti-coagulant, bromethalin and cholecalciferol.

Bromethalin

Bromethalin toxicosis is also fairly uncommon. Brand names include Assault, Trounce and Vengeance. Bromethalin works by uncoupling neural oxidative phosphorylation, resulting in demyelination and CNS dysfunction. Clinical signs include paresis or paralysis, extensor rigidity, tremors, seizures and death, and typically occur within 10-48 hours of ingestion. The toxic dose is 4.7mg/kg in the dog and 1.8mg/kg in the cat. Early treatment consists of standard decontamination, with multiple doses of activated charcoal and enemas. There is no specific antidote for bromethalin toxicity. Supportive care can be attempted, including treatment of seizures and mechanical ventilation. Death typically occurs secondary to respiratory failure. If neurologic signs develop past paresis, treatment is generally ineffective.

Anticoagulant rodenticides (ACRs)

The majority of rodenticides are from the anti-coagulant family. The mode of action is inhibition of production of Vitamin K dependent coagulation factors (II, VII, IX, and X). Second generation ACR's include brodifacoums, bromadialone, diphacinone, chlorphacinone and valone. These are long acting and require treatment for 4-6 weeks.

Ingestion results in massive hemorrhage 4-7 days after ingestion. Hemorrhage often occurs into cavities (hemoabdomen, hemothorax, hematuria), but patients can experience ecchymosis, epistaxis, hematemesis, hyphema, episcleral hemorrhage, hemomediastinum, etc. Clinical signs depend on the site of bleeding. Laboratory findings are typically related to hemorrhage. The platelet count is typically low due to loss. Early in the course of disease, prothrombin time (PT) is the most sensitive test for ACRs, with prolongations occurring within 2 days of ingestion. Activated partial thromboplastin times (aPTT) and activated clotting times (ACT) are prolonged later in the course of disease, usually after 4-7 days. However, if active hemorrhage is occurring, ACT will usually be greater than 4 minutes. Red-top clotting time is not sensitive for ACR ingestion.

Early treatment includes induction of emesis and administration of activated charcoal. If decontamination is performed early or if the owner feels that only a small amount was ingested, a PT should be checked 2 days after ingestion. If it is normal, no therapy is needed. If it is prolonged, Vitamin K1 2.2mg/kg PO BID should be instituted for the appropriate length of time. PT should always be rechecked 2 days after cessation of therapy. If the animal is actively bleeding, supportive care, fresh frozen plasma (10-15 ml/kg until PT normalizes) and blood transfusions should be instituted.

Grapes and raisins

Acute renal failure can occur in dogs following ingestion of grapes or raisins. These can be commercial products, homegrown grapes or grape pressings left over from winemaking. The toxic principle is unknown. The lowest documented toxic dose for grapes has been 0.7oz/kg, and for raisins 0.11oz/kg. However, some dogs are exposed and never show clinical signs. There have been reports of acute renal failure in cats and ferrets that have ingested grapes or raisins.

Clinical signs typically begin within 2 days of ingestion, with most dogs showing clinical signs within six hours. Typical signs include nausea, vomiting, diarrhea and anorexia. Laboratory abnormalities include evidence of dehydration and azotemia.

If presented early, standard decontamination should be performed. The clinician should recommend early and aggressive fluid diuresis at twice maintenance rates for 48 hours. If there are no increases in BUN and creatinine, fluids can be weaned after 48 hours. Overall, the prognosis is guarded, and is significantly worse in patients that develop oliguria or anuria. All cases of grape and raisin ingestion should be treated as a potential toxicity.