UMEM Educational Pearls - Toxicology

Various intial doses of naloxone (0.4 to 2 mg) are administered to reverse the signs and symptoms of opioid toxicity. However, there is limited data regarding the duration of action of naloxone is correlated to the administered dose.

A recently published retrospective study investigated whether initial naloxone doses (IV), low-dose (0.4 mg) vs. high-dose (1-2 mg), lead to different time to recurrence of opioid toxicity.

Study sample: 274 patient screened but 84 patients were included.

1. Low-dose naloxone (0.4 mg IV): 42
   • Mean age: 50
   • History of opiod/heroin use: 33 (78.6%)
   • Positive opioid/opiate on drug screening: 27 (64%)
   • Median time to repeat naloxone dose: 72 min (IQR: 46 - 139)
   • 12 patients (29%) required continuous naloxone infusion

2. High-dose naloxone (1 - 2 mg IV): 42

• Mean age: 48
• History of opiod/heron use: 32 (76.2%)
• Positive opioid/opiate on drug screening: 26 (62%)
• Median time to repeat naloxone dose: 77 min (IQR: 44 - 126)
• 17 patients (41%) required continuous naloxone infusion

Higher rate of adverse effects (withdrawal symptoms - vomiting, agitation, tachycardia, etc.) were observed in high-dose group (41% vs. 31%) but this was not statistically signficant. 

Conclusion:

1. High-dose naloxone (1 - 2 mg) does not result in longer duration of reversal of opioid toxicity.
2. Duration of opioid toxicity reversal by naloxone administration were similar to previously reported duration of action of naloxone (30 to 90 min).
3. Note: there are several lmitations to the study study including retrospective design - documentation issues, small sample size, patient selection - patients were included if positive response to naloxone was observed, unknown opioid exposure, variable dosing in high-dose group (1 to 2 mg vs. 0.4 mg) and naloxone was given via IV only.   

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Elevated transaminases are found in both rhabdomyolysis and delayed acetaminophen (APAP) toxicity. Establishing the cause of elevated transaminase can be difficult when there is unclear history of acetaminophen ingestion.

A retrospective study of patients with delayed acetaminophen toxicity or rhabdomyolysis from 2006 to 2011 was recently published.

The authors compared AST/ALT, CK/AST and CK/ALT ratio of 

• 160 in the rhabdomyolysis group
• 68 in the acetaminophen overdose (all)
• 29 in the delayed acetaminophen overdose group

Results

AST/ALT ratio

• Rhabdomyolysis group: 1.66
• APAP overdose (all): 1.38
• Delayed APAP overdose: 1.3

CK/AST ratio

• Rhabdomyolysis group: 21.3
• APAP overdose (all): 5.49
• Delayed APAP overdose: 3.8

CK/ALT ratio

• Rhabdomyolysis group: 37.1
• APAP overdose (all): 5.77
• Delayed APAP overdose: 5.03

Conclusion

• Significantly higher ratio of AST/ALT, CK/AST and CK/ALT were found in rhabdomyolysis patients than delayed APAP overdose patients.
• These finding are based on small study population and need further validation/research before clinical application.

Sulfonylureas are commonly used oral hypoglycemic agents for type II diabetes. Agents on the market include glipizide (Glucotrol), glyburide (Micronase, Glynase, Dibeta) and glymepiride (Amaryl). These agents exert their effect by stimulation of insulin release from the pancreatic beta islet cells. Following overdose, hypoglycemia is usually seen within a few hours of ingestion and can be prolonged and profound. First line treatment for rapid correction of severe hypoglycemia is administration of an intravenous bolus of concentrated dextrose. However, use of dextrose infusion in attempt to maintain euglycemia is problematic as it can cause further release of insulin and rebound hypoglycemia. Octreotide ia a long acting synthetic somatostain analogue, blocks insulin secretion and has been shown to prevent recurrence of hypogylcemia better than placebo.

Bottom Line:

• Octreotide is the antidote of choice for sulfonylurea poisoning. Its use greatly simplifies management by avoiding the need for a central line, prolonged ICU admit, and frequent monitoring.
• Bolus 50 μg IV followed by an infusion of 25–50μg/h or give100 mcg subcutaneously with additional doses at 6-12 hour intervals for recurrent hypoglycemia. Octreotide has similar bioavailability by SC and IV route. It's duration of action can extend from 6 to 12 hours with SC use.
• After stopping Octreotide monitor for 12-24 hours for rebound hypoglycemia.

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From 1960s to 1970s, physostigmine was routinely administered as part of the "coma cocktail." Since the publication of two cases by Pentel (1980) that resulted in asystole after administration of physostigmine in TCA poisoned patient, its use has declined significantly.

However, physostigmine still possess limited but clinically useful role in the management of patients with antimuscarinic/anticholinergic induced delirium.

Recently, a prospective observational study was performed in the use of physostigmine when recommended by a regional poison center.

In 1 year study period, physostigmine was recommended by a regional poison center in 125 of 154 patients with suspected antimuscarinic/anticholinergic toxicity. 

common exposures were

1. antihistamines (68%)
2. analgesics (19%)
3. antipsychotics (19%)

57 of 125 patients received physostigmine per treating team.

• median dose of physostigmine administered: 2 mg

Of the remaining patients,

• 35 patients did not receive any sedative agents
• 55 received benzodiazepines (56%)
• others received propofol (n=10), haloperidol (n=8), olanzapine (n=4), dexmedetomidine (n=3), etc.

Delirium control

• Physostigmine group 79% (45 of 57)
• No-physostigmine group: 36% (35 of 97)

Adverse events (physostigmine group vs. non-physo group) - no statistically significant difference.

• Intubation (n=7): 2 (3.5%) vs. 5 (5.2%)
• physical restraints (n=10): 3 (5.3%) vs. 7 (7.2%)
• vomiting (n=4): 3 (5.3%) vs. 1 (1.0%)

Conclusion:

Physostigmine can safely control antimuscarinic/anticholinergic-induced delirium.

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Acutely agitated patients in the emegency room receive single or combination of benzodiazepine (lorazepam vs. midazolam) and antipsychotic (e.g. haloperidol) agents. Recently, use of ketamine has also been advocated to sedate agitated patients.

A recently published article compared IM administration several medications to treat acutely agitated patients in the ED. According to established protocol, each medication was administered in predetermined 3 week blocks:

1. Haloperidol (5 mg)
2. Ziprasidone (20 mg)
3. Olanzapine (10 mg)
4. Midazolam (5 mg)
5. Haloperidol (10 mg)

Results

N=737 with median age of 40 years, 72% men.

Midazolam resulted in greater proportion of patients with "adequate" sedation (altered mentatl status scale <1) compared to antipsychotics at 15 min post administration. Among antipsychotics, olanzapine resulted in greater proportion of patient with sedation. 

• Midazolam (71%)
• Haloperidol - 5 mg (40%)
• Haloperidol - 10 mg (42%)
• Olanzapine (61%)
• ziprasidone (52%)

Adverse effect were limited

• extrapyramidal AE: 0.3%
• hypotension 0.5%
• hypoxemia 1%
• intubation 0.5%

Conclusion:

Midazolam 5 mg IM achieve more effective sedation at 15 min in agitated ED patients than antipsychotics.

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Methylene Blue is a dye that was synthesized in the late 1800s as an antimalarial drug. After the emergence of chloroquine its use loss favor partly due to unpopular side effects of temporarily turning the urine, other body fluids, and the sclera blue. Methylene blue is primarily known as a highly effective fast acting antidote for methemboglobinemia. Over the past few years, it has become an important therapeutic modality with expanding uses in cardiac surgery and critical care.  As a potent inhibitor of nitric oxide mediated guanylate cyclase induced endothelium vascular smooth muscle relaxation, it has been shown to be effective in increasing arterial blood pressure and cardiac function in several clinical states, such as septic shock and calcium channel blocker poisoning.

BOTTOM LINE:

• Methylene blue should be considered for treatment of refractory shock from calcium channel and beta blocker poisoning.

• Clinical improvement in refractory hypotension and reduction of vasopressor dose has been described in several poisoning cases. 

• Recommended dose is 1–2 mg/kg injection with effects seen within 1 hour.

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On May 3, the FDA approved adexanet alfa, the reversal agent for factor Xa inhibitors - apixaban and rivaroxaban. It received both U.S. Orphan Drug and FDA Breakthrough Therapy designations. 

Unlike indarucizumab (a monoclonal antibody fragment) to reverse dabigatran (direct thrombin inhibitor) associated bleeding, adexanet alfa is a recombinant modified human factor Xa decoy protein. 

A phase 3 study showed that adexanet alfa decreased the anti-factor Xa activity of rivaroxaban by 92% from baseline and by 94% in apixaban treated participants.

ANNEXA-4 study involving participants with acute major bleeding (GI and intracranial) showed a significant decrease in the anti-factor Xa activity after the bolus dose of adexanet alfa and "effective" hemostasis was noted in 79% of the participants at 12 hours post infusion.

Andexanet alfa is expected to become available in June 2018.

Despite initial excitement for the use of intravenous lipid emulsion (ILE) therapy as an antidote for serious poisonings due to lipohphilic drugs there remains an absence of evidence combined with an incomplete understanding of its efficacy, mechanisms of action, safety, and analytical interferences to recommend its use except in a few clinical scenarios.

The lipid emulsion workgroup performed a comprehensive analysis of four systematic reviews and based recommendations from consensus of expert panelists from the American Academy of Clinical Toxicology, the European Association of Poison Centres and Clinical Toxicologists, the American College of Medical Toxicology, the Asia Pacific Association of Medical Toxicology, the American Association of Poison Control Centers, and the Canadian Association of Poison Control Centers. Toxins evaluated had to have a minimum of three human cases reported in the literature.They concluded that ILE could be indicated for the following clinical situations:

•  In Bupivacaine poisoning resulting in cardiac arrest or life threatening toxicity (dysrhythmias, VTach  with compromised organ perfusion, VFib, status epilepticus, and/or hypotension with organ compromise defined as  increased lactate concentration, acute kidney injury, increased troponin, altered mental status, or decreased capillary refill) ILE is recommended after standard ACLS is started  and if other therapies fail or as last resort.

• In life-threatening toxicity due to other local anesthetics,  ILE recommended if other therapies fail/in last resort

• In cardiac arrest due to toxicity from Amitriptyline (or other tricyclic antidepressants), lipid soluble and non-lipid soluble Beta-receptor antagonists,  Bupropion, Calcium channel blockers (diltiazem, verapamil and dfihydropyridines), Cocaine, Diphenhydramine, Lamotrigine,  Baclofen, Ivermectin and other Insecticides, Malathion and other Pesticides, Olanzapine and other Antipsychotics, and SSRIs.

• Most common regimen of ILE was a bolus of 1.5 mL/kg of ILE 20% followed by infusion of 0.25 mL/kg/min

• The use of ILE with extracorpeal membrane oxygenation may cause fat deposition in the circuit and increase blood clot formation causing malfunction and limitation of use of this potentially life saving modality. This should be considered if VA-ECMO is a treatment option.

The Bottom Line:

The use of Intravenous Lipid Emulsion in severe poisoning is recommended only for a few poisoning scenarios and was based on very low quality of evidence, and consideration of risks and benefits, adverse effects, laboratory interferences as well as related costs and resources.

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Non-pharmaceutical fentanyl (NPF) is a major contributor to opioid overdoses and overdose fatality. In certain urban areas such as Vancouver, over 80% of heroin samples contain NPF.  For isolated heroin overdose ED patients, they can be safely discharged after brief observation period (~2 hours). However,  “safe” observation time for fentanyl is unknown.

Recently, a retrospective study evaluating the safe observation period in 1009 suspected (uncomplicated) fentanyl overdose ED visits (827 unique patients).

Results:

 In the field:

• 476 (47.1%) received bystander naloxone
  • 422 (44.1%) had field GCS of 15
  • 547 (57.2%) had pulse oximetry of >= 95%.
•  EMS administered naloxone to 546 (57.1%) patients (mean dose 0.4 mg IV)

In the ED:

• 16 patients received additional naloxone in the ED
• Mean length of stay: 173 minutes (IQR: 101 to 267 minutes)
• 90% of the patients were discharged within 380 minute.
• One patient was admitted and one patient died after discharge within 24 hours.

Conclusion:

• Majority of the patients were safely discharged after 3 - 4 hours after receiving naloxone and if able to maintain GCS 15 with oxygen level 95% while able to ambulate normally.
• However, some patient may require up to 6 hours of observation.  

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Bradycardias caused by poisoning are due to the toxin's effects on cardiovascular receptors and cellular channels and transport mechanisms and are often refractory to standard ACLS drugs. The most common drug classes responsible for bradycardias are calcium channel and beta blockers and digoxin (cardiac glycosides). Sodium channel blockers, clonidine, and opiates also can cause bradycardias. Antidotes are as follows:

• Glucagon 5-10mg IV bolus followed by 1-5 mg/hr (Always pretreat with antiemetic) - Beta Blockers
• Calcium infusion 1-3 grams IV Bolus - Calcium Channel Blockers
• High Dose Insulin Euglycemic therapy of reg insulin 0.5-2 unit/kg Bolus (ie. 100 Units) with D50 IV bolus followed by reg insulin 0.5-1 units/kg/hr and dextrose 0.5 grams/kg/hr - Calcium channel and Beta Blockers
• **Intravenous Lipid Emulsion therapy bolus 1.5 mL/kg of ILE 20% followed by an infusion of 0.25 mL/kg/min-  Very small subset of toxins. See below.
• Atropine 2mg IV - Acetylcholinestrase inhibitors (Organophosphates)
• Sodium Bicarbonate 1-3 amps IV - Sodium Channel Blockers
• Digibind  for acute toxicity10 vials IV (20 Vials in cardiac arrest) and for chronic toxicity 2 vials and repeat as needed - Cardiac gylcosides
• Narcan 2 mg IV repeat boluses up to 10 mg- Opiates and Clonidine

** ILE is recommended only in life threatening poisonings where other accepted therapies have been use first or in cardiac arrest clinical scenarios. 

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Clonidine, (central alpha-2 receptor agonist) can produce opioid-like toxidrome in addition to its cardiac effects (bradycardia and hypotension). Previous studies have shown that naloxone has variable (~40%) success in reversing CNS/respiratory depression and cardiac effect.

A recent retrospective study (n=51) of pediatric poisoning showed that administration of 5 to 10 mg had improved reversal of clonidine toxicity.

Total of 51 somnolent patients: 5- 10 mg of naloxone reversed 40 patients

• 22 patients awoke with 6 mg or less
• Bradycardia reversed in 17 of 44 patients
• Hypotension reversed in 7 of 11 patients

There was no adverse effect from naloxone administration.

Repeat administration of naloxone was required in some patients.

Bottom line

• For pediatric clonidine toxicity, consider initial naloxone dose of 5 mg IV. 

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Takeaways

In the past couple of weeks, there have been reports from Illinois about patients using adulterated synthetic cannabinoids, resulting in elevated INR and bleeding. To date, there are approximately 70 cases including 3 fatalities. Brodifacoum, a long-acting vitamin K mediated anticoagulant (similar to warfarin) has been identified in 10 cases. Brodifacoum is frequently used as rodenticide.

This week, Maryland Poison Center received our first notification of a patient with bleeding and elevated INR due to suspected adulterated synthetic cannabinoid use.

When evaluating our patient population:

• Ask about synthetic cannabinoid use in patients with unexplained bleeding and elevated INR
• Carefully examine patients with synthetic cannabinoid intoxication for any signs of bleeding, bruising or petechiae.  
   

Patient management of suspected cases:

• ACTIVELY bleeding:
  • Fresh frozen plasma
  • Activated prothrombin complex concentrate (KCentra®) in life threatening bleeding.
  • Vitamin K 10 mg IV
  • *** Start oral vitamin K at 50 mg TID and titrate to goal INR < 2 ***
• NOT bleeding and INR < 10: vitamin K 50 mg PO BID with titration if needed.
• NOT bleeding and INR > 10: vitamin K 50 mg PO TID with titration if needed.

Patient can be discharged when INR < 2 is achieved with oral vitamine K regimen only (without recent FFP infusion).

Review of published cases highlights that most patients are started on a median doses of 100 mg/day (range: 15 - 600 mg) and stabilize on a PO regimen of 50-100 mg/day. Prolonged PO vitamin K course of 2 – 3 months or longer should be anticipated.

Pease call the Maryland Poison Center at 1-800-222-1222 as we are working with the Maryland Department of Health and CDC to track these cases. 

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Recently, an ex-Russian spy and his daughter were poisoned in Salisbury, England using a Soviet nerve agent called Novichok. He joins a list of defectors and ex-spies who's poisoning have been connected to Russia.

Nerve agents are organophosphate compounds, similar to the commercially available pesticides, but significantly more potent. Nerve agents such as VX take seconds to minutes to irreversibly inhibit acetylcholinesterase by “aging” and result in clinical toxicity. 

Signs and symptoms

• Muscarinic: DUMBELS or SLUDGE and Killer B's
• Nicotinic: muscle weakness & paralysis

Treatment

• Decontamination
• Atropine – 2 mg IV and double the dose every 3 – 5 minutes until clearing of bronchorrhea, bronchospasm and bradycardia
• Pralidoxime – reverses inhibition of acetylcholinesterases that are not aged

Signs and symptoms of acute cyanide poisoning are not well characterized due to its rare occurrence.  Commonly mentioned characteristics of bitter almond odor and cherry red skin have poor clinical utility.

Recently published review of 65 articles (102 patients) showed that most patients experienced following signs and symptoms:

1. Unresponsive: 78%
2. Respiratory failure: 73%
3. Hypotension: 54%
4. Cardiac arrest: 20%
5. Seizure: 20%
6. Cyanosis: 15%
7. Odor: 15%
8. Cherry red skin: 11%

There is no clear toxidrome for cyanide poisoning.

In a poisoned patient, health care providers should consider cyanide in their differential diagnosis in the presence of severe metabolic and lactic acidosis (lactic acid > 8 in isolated cyanide poisoning or > 10 in smoke/fire victim).

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A leading cause of cardiac arrest in patients 40 years and younger is due to drug poisoning.  Adverse cardiovascular events (ACVE) such as myocardial injury (by biomarker or ECG), shock (hypotension or hypoperfusion requiring vasopressors), ventricular dysrhythmias (ventricular tachycardia/fibrillation, torsade de pointes), and cardiac arrest (loss of pulse requiring CPR) are responsible for the largest proportion of morbidity and mortality overdose emergencies. Clinical predictors of adverse cardiovascular events in drug overdose in recent studies include:

• QTc prolongation on presentation ECG ( > 500 msec )
• Prior history of either coronary artery disease or congestive heart failure
• Metabolic acidosis (elevated serum lactate)

Bottom line:

Obtain ECG and perform continuous telemetry monitoring in overdose patients with above risk factors. Patients with two or more risk factors have extremely high risk of in-hospital adverse cardiovascular events and intensive care setting should be considered.

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Abnormal ocular movement (e.g. nystagmus) can often be observed in select CNS pathology.

Certain drugs/toxin overdose can also induce nystagmus.

• Anti-epileptics: carbamazepine, lamotrigine, topiramate, phenytoin
• Ethanol
• Ketamine, phencyclidine (PCP), dextromethorphan – vertical or rotary nystagmus
• Serotonergic syndrome/5-HT agonists – opsoclonus
• Monoamine oxidase inhibitors – ping-pong nystagmus
• Lithium
• Scorpion envenomation 

In an "unknown" intoxication, physical exam findings such as nystagmus may help narrow the identity of the suspected ingestion/overdose.

Bupropion (Wellbutrin, Zyban) is unique monocyclic antidepressant and smoking cessation agent that is structurally similar to amphetamines.  Bupropion blocks dopamine and norepinephrine reuptake and antagonizes acetylcholine at nicotinic receptors.

• One of the most common causes of drug-induced seizures.
• Sinus tachycardia is the most frequently seen cardiac effects with overdose.
• QTc prolongation and ventricular dysrhythmias can occur in severe overdose. New evidence supports this is not related to cardiac sodium channel block but likely due to blockade of the delayed rectifying (ikr) potassium channel and gap junction inhibition in the myocardium simulating effects class IA effect.

Bottom line:

Bupropion is a common cause of drug induced seizures but in severe overdose can also cause prolonged QTc and wide complex ventricular dysrhythmia that may be responsive to sodium bicarbonate. All patients with an overdose of bupropion should have an ECG performed and cardiac monitoring to watch for conduction delays and life-threatening arrhythmias.

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Question

47 year old woman presents with cough, headache, weakness, and low grade fever. Her symptoms have been present for several days. Vital signs are temperature 99.9 F, HR 96, RR 16, BP 140/88, Pulse Ox 98%.  Physical exam is nonfocal. She is Influenza negative. She is treated with Ibuprofen and oral fluids.  Upon discharge she mentions she is having difficulty hearing and feels dizzy. Upon further questioning she admits to ringing in her ears. What tests should you order?

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Acute liver failure carries a high morbidity without liver transplantation. Liver support systems can act as “bridge” until an organ becomes available for the transplant procedure or until the liver recovers from injury. Artificial liver support systems temporally provide liver detoxification utilizing albumin as scavenger molecule to clear the toxins without providing synthetic functions of the liver (coagulation factors). One of the most widely used devices is the Molecular Adsorbent Recirculating System (MARS).This system has 3 different fluid compartments: blood circuit, albumin with charcoal and anion exchange column, and a dialysate circuit that removes protein bound and water soluble toxins with albumin.

• Mars has been used in several case reports to treat acetaminophen, Amanita phalloides,Phenytoin, lamotrigine, theophylline, and calcilum channel blockers poisonings.
• All the extracorporeal liver assist devices are able to remove biological substances (ammonia, urea, creatinine, bilirubin, bile acids, amino acids, cytokines, vasoactive agents) but the real impact on the patient's clinical course has still to be determined.

Bottom Line

MARS therapy could be a potentially promising life saving treatment for patients with acute poisoning from drugs that have high protein-binding capacity and are metabolized by the liver, especially when concomitment liver failure. Consider consultation and transfer of patients to liver center.

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Acetaminophen (APAP) overdose is the leading cause of liver failure in the U.S. and Europe. Large APAP ingestion can result in hepatotoxicity despite the early initiation of n-acetylcysteine (NAC). 

A recently published study from Austrialia investigated the effect of activate charcoal and increasing the NAC dose for large APAP overdose patients (3rd bag: 100 to 200 mg/kg over 16 hours) during first 21 hours of NAC therapy

acetaminophen ratio (first APAP level taken between 4 to 16 hour post ingestion / APAP level on the Rumack nomogram line at that time point) was determined to compare APAP levels at different time points among study sample

e.g.  

first APAP level at 4 hour post ingestion = 400

APAP level on the Rumack APAP nomogram at 4 hour post ingestion = 150

APAP ratio = 400/150 = 2.67

Findings:

1. Activated charcoal (AC): if given within 4 hours, AC significantly decreased the APAP ratio (OR: 1.4 vs. 2.2)
2. Increased dose of NAC during the first 21 hour significantly decreased the risk of hepatotoxicity (OR: 0.27; 95% CI: 0.08 - 0.94).

Conclusion: 

1. Administration of AC in patients with history of large APAP overdose (>=40 gm) within 4 hour of ingestion can still be beneficial.
2. Increasing NAC dosing (3rd bag in first 21 hour thearpy) may decrease the risk of hepatotoxicity. 

Note: Any increase in NAC dosing from the standard 21 hour therapy should be performed after consulting your regional poison center.

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